Heteroaryls and uses thereof

ABSTRACT

This invention provides compounds of formula IA-i-a or IB-i-a and subsets thereof: 
     
       
         
         
             
             
         
       
     
     wherein Z, HY, R 1 , R 2 , R 3 , G 1 , W, n, and A and subsets thereof are as described in the specification. The compounds are inhibitors of PI3K and are thus useful for treating proliferative, inflammatory, or cardiovascular disorders.

The present application claims the benefit of U.S. patent applicationSer. No. 13/207,753 (now U.S. Pat. No. 8,796,268), which claims benefitof U.S. Provisional Application Ser. No. 61/372,594, filed Aug. 11,2010, and U.S. Provisional Application Ser. No. 61/438,375, filed Feb.1, 2011, each of which is hereby incorporated by reference in itsentirety.

BACKGROUND OF THE INVENTION

Phosphatidylinositol 3-kinase (PI3K) is a family of lipid kinases thatphosphorylate phosphatidylinositol at the 3′ position of the inositolring. PI3K is comprised of several classes of genes, including Class IA,IB, II and III and some of these classes contain several isoforms(reviewed in Engelman et al., Nature Review Genetics 7:606-619 (2006)).Adding to the complexity of this family is the fact that PI3Ks functionas heterodimers, comprising a catalytic domain and a regulatory domain.The PI3K family is structurally related to a larger group of lipid andserine/threonine protein kinases known as the phosphatidylinositol3-kinase like kinases (PIKKs), which also includes DNA-PK, ATM, ATR,mTOR, TRRAP and SMG1.

PI3K is activated downstream of various mitogenic signals mediatedthrough receptor tyrosine kinases, and subsequently stimulates a varietyof biological outcomes; including increased cell survival, cell cycleprogression, cell growth, cell metabolism, cell migration andangiogenesis (reviewed in Cantley, Science 296:1655-57 (2002); Hennessyet al., Nature Reviews Drug Discovery 4:988-1004 (2005); Engelman etal., Nature Review Genetics 7:606-619 (2006)). Thus, PI3Khyper-activation is associated with a number of hyper-proliferative,inflammatory, or cardiovascular disorders; including cancer,inflammation, and cardiovascular disease.

There are a number of genetic aberrations that lead to constitutive PI3Ksignaling; including activating mutations in PI3K itself (Hennessy etal., Nature Reviews Drug Discovery 4:988-1004 (2005); reviewed in Baderet al., Nature Reviews Cancer 5:921-9 (2005)); RAS (reviewed in DownwardNature Reviews Cancer 3:11-22 (2003)) and upstream receptor tyrosinekinases (reviewed in Zwick et al., Trends in Molecular Medicine 8:17-23(2002)) as well as inactivating mutations in the tumor suppressor PTEN(reviewed in Cully et al., Nature Reviews Cancer 6:184-92 (2006)).Mutations in each of these gene classes have proven to be oncogenic andare commonly found in a variety of cancers.

The molecules defined within this invention inhibit the activity ofPI3K, and therefore may be useful for the treatment of proliferative,inflammatory, or cardiovascular disorders. Cases where PI3K pathwaymutations have been linked to proliferative disorders where themolecules defined within this invention may have a therapeutic benefitinclude benign and malignant tumors and cancers from diverse lineage,including but not limited to those derived from colon (Samuels et al.,Science 304:554 (2004); reviewed in Karakas et al., British Journal ofCancer 94: 455-59 (2006)), liver (reviewed in Karakas et al., BritishJournal of Cancer 94: 455-59 (2006)), intestine (reviewed in Hennessy etal., Nature Reviews Drug Discovery 4:988-1004 (2005)), stomach (Samuelset al., Science 304:554 (2004); reviewed in Karakas et al., BritishJournal of Cancer 94: 455-59 (2006)), esophagus (Phillips et al.,International Journal of Cancer 118:2644-6 (2006)); pancreas (reviewedin Downward Nature Reviews Cancer 3:11-22 (2003)); skin (reviewed inHennessy et al., Nature Reviews Drug Discovery 4:988-1004 (2005)),prostate (reviewed in Hennessy et al., Nature Reviews Drug Discovery4:988-1004 (2005)), lung (Samuels et al., Science 304:554 (2004);reviewed in Karakas et al., British Journal of Cancer 94: 455-59(2006)), breast (Samuels et al., Science 304:554 (2004); Isakoff et al.,Can Res 65:10992-1000 (2005); reviewed in Karakas et al., BritishJournal of Cancer 94: 455-59 (2006)), endometrium (Oda et al., Can Res65:10669-73 (2005); reviewed in Hennessy et al., Nature Reviews DrugDiscovery 4:988-1004 (2005)), cervix (reviewed in Hennessy et al.,Nature Reviews Drug Discovery 4:988-1004 (2005)); ovary (Shayesteh etal., Nature Genetics 21:99-102 (1999); reviewed in Karakas et al.,British Journal of Cancer 94: 455-59 (2006)), testes (Moul et al., GenesChromosomes Cancer 5:109-18 (1992); Di Vizio et al., Oncogene 24:1882-94(2005)), hematological cells (reviewed in Karakas et al., BritishJournal of Cancer 94: 455-59 (2006); Hennessy et al., Nature ReviewsDrug Discovery 4:988-1004 (2005)), pancreas (reviewed in Downward NatureReviews Cancer 3:11-22 (2003)), thyroid (reviewed in Downward NatureReviews Cancer 3:11-22 (2003); reviewed in Hennessy et al., NatureReviews Drug Discovery 4:988-1004 (2005)); brain (Samuels et al.,Science 304:554 (2004); reviewed in Karakas et al., British Journal ofCancer 94: 455-59 (2006)), bladder (Lopez-Knowles et al., CancerResearch 66:7401-7404 (2006); Hennessy et al., Nature Reviews DrugDiscovery 4:988-1004 (2005)); kidney (reviewed in Downward NatureReviews Cancer 3:11-22 (2003)) and Head and Neck (reviewed in Engelmanet al., Nature Reviews Genetics 7:606-619 (2006)).

Other classes of disorders with aberrant PI3K pathway signaling wherethe molecules defined within this invention may have a therapeuticbenefit include inflammatory and cardiovascular diseases, including butnot limited to allergies/anaphylaxis (reviewed in Rommel et al., NatureReviews Immunology 7:191-201 (2007)), acute and chronic inflammation(reviewed in Ruckle et al., Nature Reviews Drug Discovery 5:903-12(2006); reviewed in Rommel et al., Nature Reviews Immunology 7:191-201(2007)), rheumatoid arthritis (reviewed in Rommel et al., Nature ReviewsImmunology 7:191-201 (2007)); autoimmunity disorders (reviewed in Ruckleet al., Nature Reviews Drug Discovery 5:903-12 (2006)), thrombosis(Jackson et al., Nature Medicine 11:507-14 (2005); reviewed in Ruckle etal., Nature Reviews Drug Discovery 5:903-12 (2006)), hypertension(reviewed in Ruckle et al., Nature Reviews Drug Discovery 5:903-12(2006)), cardiac hypertrophy (reviewed in Proud et al., CardiovascularResearch 63:403-13 (2004)), and heart failure (reviewed in Mocanu etal., British Journal of Pharmacology 150:833-8 (2007)).

Vacuolar Protein Sorting 34 (VPS34) is the sole Class III PI3K familymember. VPS34 functions in the formation and trafficking of multipleintracellular vesicles, including vacuoles, endosomes, multivessicularbodies, lysosomes and autophagosomes (reviewed in Backer Biochem J 2008;Yan and Backer Biochem J 2007). VPS34 carries out these activities byphosphorylating PtdIns forming PtdIns3P, resulting in the recruitmentand localization of a variety of FYVE and PX domain containing effectorproteins that facilitate vesicular formation, elongation and movement.At a cellular level, inhibition of VPS34 results in defects in proteinsorting and autophagy. Broadly defined, autophagy is a regulated processwhereby cells catabolize subcellular components targeted for degradationby enclosing them in double-membrane vesicles which then fuse withlysosomes. Autophagy has been best characterized as occurring duringtimes of nutrient deprivation, but also plays a role in normal cellularand tissue homeostasis and functions, including the development ofmultiple tissue types, the immune response, clearance of neuronalaggregates and tumor suppression. In addition to functioning in vesicleformation and movement, VPS34 may also participate in several signaltransduction pathways (reviewed in Backer Biochem J 2008). Given thatVPS34 plays an important role in many critical cellular processesincluding autophagy, inhibitors of VPS34 may have therapeuticapplication in a number of diseases, including but not limited tocancer, muscular disorders, neurodegeneration, inflammatory disease,infectious disease and other age related illnesses (reviewed in Shintaniand Klionshy Science 2004; Kondo et al Nat Rev Cancer 2005; Delgato etal Immunol Rev 2009).

Clearly, it would be beneficial to provide novel PI3K inhibitors thatpossess good therapeutic properties, especially for the treatment ofproliferative, inflammatory, or cardiovascular disorders.

1. General Description of Compounds of the Invention

This invention provides compounds that are inhibitors of PI3K, andaccordingly are useful for the treatment of proliferative, inflammatory,or cardiovascular disorders. In one embodiment, the compounds of thisinvention are represented by formula IA-a or IB-a:

or a pharmaceutically acceptable salt thereof, wherein:

Z is S or Se;

R¹ is CY, —C(O)N(R³)₂, —C(O)OR³, —C(O)(NH)OH, —C(═NH)NHOH,—C(O)NR³N(R³)₂, —C(═N—NH₂)NH₂, —C(═N)N(R³)₂, wherein:

-   -   CY is

wherein:

-   -   G₂ is —N═, ═N—, or —N(R^(3′))—, wherein:    -   each occurrence of R³ and R^(3′) is independently hydrogen or an        optionally substituted C₁₋₆ aliphatic, wherein:    -   X₁, X₂, and X₃, are each independently N, NR^(3′), O, S, or CR⁴,        provided that only one of X₁, X₂, or X₃ may be O, S, or NR^(3′);        -   each occurrence of R⁴ is independently hydrogen, —CN,            halogen, —Z₃—R⁶, or an optionally substituted group selected            from C₁₋₆ aliphatic, or 3-10-membered cycloaliphatic,            wherein:        -   Z₃ is selected from an optionally substituted C₁₋₃ alkylene            chain, —O—, —N(R^(4a))—, —S—, —S(O)—, —S(O)₂—, —C(O)—,            —CO₂—, —C(O)NR^(4a)—, —N(R^(4a))C(O)—, —N(R^(4a))CO₂—,            —S(O)₂NR^(4a)—, —N(R^(4a))S(O)₂—, —OC(O)N(R^(4a))—,            —N(R^(4a))C(O)NR^(4a)—, —N(R^(4a))S(O)₂N(R^(4a))—, or            —OC(O)—;        -   R^(4a) is hydrogen or an optionally substituted C₁₋₄            aliphatic, and        -   R⁶ is hydrogen or an optionally substituted group selected            from C₁₋₆ aliphatic, 3-10-membered cycloaliphatic,            4-10-membered heterocyclyl having 1-5 heteroatoms            independently selected from nitrogen, oxygen, or sulfur,            6-10-membered aryl, or 5-10-membered heteroaryl having 1-5            heteroatoms independently selected from nitrogen, oxygen, or            sulfur;        -   or wherein two adjacent occurrences of R^(3′) or R⁴, taken            together with the atom to which they are bound, form an            optionally substituted fused group selected from            5-6-membered aryl, or 5-6-membered heteroaryl having 1-5            heteroatoms independently selected from nitrogen, oxygen, or            sulfur;

Ring A is a group selected from 3-10-membered cycloaliphatic,4-10-membered heterocyclyl having 1-5 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-memberedheteroaryl having 1-5 heteroatoms independently selected from nitrogen,oxygen, or sulfur;

each occurrence of R² is independently —R^(12a), -T₂-R^(12d), or—V₂-T₂-R^(12d), and:

-   -   each occurrence of R^(12a) is independently halogen, —CN, —NO₂,        —R^(12c), —N(R^(12b))₂, —OR^(12b), —SR^(12c), —S(O)₂R^(12c),        —C(O)R^(12b), —C(O)OR^(12b), C(O)N(R^(12b))₂, —S(O)₂N(R^(12b))₂,        —OC(O)N(R^(12b))₂, —N(R^(12e))C(O)R^(12b),        —N(R^(12e))SO₂R^(12c), —N(R^(12e))C(O)OR^(12b),        —N(R^(12e))C(O)N(R^(12b))₂, or —N(R^(12e))SO₂N(R^(12b))₂, or two        occurrences of R^(12b), taken together with a nitrogen atom to        which they are bound, form an optionally substituted        4-7-membered heterocyclyl ring having 0-1 additional heteroatoms        selected from nitrogen, oxygen, or sulfur;    -   each occurrence of R^(12b) is independently hydrogen or an        optionally substituted group selected from C₁-C₆ aliphatic,        3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having        1-5 heteroatoms independently selected from nitrogen, oxygen, or        sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having        1-5 heteroatoms independently selected from nitrogen, oxygen, or        sulfur;    -   each occurrence of R^(12c) is independently an optionally        substituted group selected from C₁-C₆ aliphatic, 3-10-membered        cycloaliphatic, 4-10-membered heterocyclyl having 1-5        heteroatoms independently selected from nitrogen, oxygen, or        sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having        1-5 heteroatoms independently selected from nitrogen, oxygen, or        sulfur;    -   each occurrence of R^(12d) is independently hydrogen or an        optionally substituted from 3-10-membered cycloaliphatic,        4-10-membered heterocyclyl having 1-5 heteroatoms independently        selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl,        or 5-10-membered heteroaryl having 1-5 heteroatoms independently        selected from nitrogen, oxygen, or sulfur;    -   each occurrence of R^(12e) is independently hydrogen or an        optionally substituted C₁₋₆ aliphatic group;    -   each occurrence of V₂ is independently —N(R^(12e))—, —O—, —S—,        —S(O)—, —S(O)₂—, —C(O)—, —C(O)O—, —C(O)N(R^(12e))—,        —S(O)₂N(R^(12e))—, —OC(O)N(R^(12e))—, —N(R^(12e))C(O)—,        —N(R^(12e))SO₂—, —N(R^(12e))C(O)O—, —N(R^(12e))C(O)N(R^(12e))—,        —N(R^(12e))SO₂N(R^(12e))—, —OC(O)—, or —C(O)N(R^(12e))—O—; and

T₂ is an optionally substituted C₁-C₆ alkylene chain wherein thealkylene chain optionally is interrupted by —N(R¹³)—, —O—, —S—, —S(O)—,—S(O)₂—, —C(O)—, —C(O)O—, —C(O)N(R¹³)—, —S(O)₂N(R¹³)—, —OC(O)N(R¹³)—,—N(R¹³)C(O)—, —N(R¹³)SO₂—, —N(R¹³)C(O)O—, —N(R¹³)C(O)N(R¹³)—,—N(R¹³)S(O)₂N(R¹³)—, —OC(O)—, or —C(O)N(R¹³)—O— or wherein T₂ or aportion thereof optionally forms part of an optionally substituted 3-7membered cycloaliphatic or heterocyclyl ring, wherein R¹³ is hydrogen oran optionally substituted C₁₋₄aliphatic group;

n is 0 to 4;

W is selected from —C(R⁷)₂—, —C(═C(R⁷)₂)—, —C(R⁷)₂O—, —C(R⁷)₂NR^(7a)—,—O—, —N(R^(7b))—, —S—, —S(O)—, —S(O)₂—, —C(O)—, —C(O)NR^(7a)—, or—N(R^(7a))C(O)—, wherein:

-   -   each occurrence of R⁷ is independently hydrogen, or an        optionally substituted group selected from C₁₋₆ aliphatic,        6-10-membered aryl, 5-10-membered heteroaryl having 1-5        heteroatoms independently selected from nitrogen, oxygen, or        sulfur, —N(R^(7b))₂, —OR^(7a), —SR^(7a), halo, or —CN;    -   each occurrence of R^(7a) is independently hydrogen or        optionally substituted C₁₋₆ aliphatic or optionally substituted        C₃₋₆ cycloaliphatic;    -   each occurrence of R^(7b) is independently hydrogen, optionally        substituted C₁₋₆ aliphatic, optionally substituted C₃₋₆        cycloaliphatic, —C(O)R^(7a), —C(O)OR^(7a), S(O)R^(7a), or        —S(O)₂R^(7a); or    -   wherein any two occurrences of R⁷, R^(7a), or R^(7b) taken        together with the atom to which they are bound, form an        optionally substituted group selected from a 3-6-membered        cycloaliphatic ring, 6-10-membered aryl, 3-6-membered        heterocyclyl having 1-5 heteroatoms independently selected from        nitrogen, oxygen, or sulfur, or 5-10-membered heteroaryl having        1-5 heteroatoms independently selected from nitrogen, oxygen, or        sulfur;    -   or wherein any two occurrences of R^(7a) and R², or R^(7b) and        R² taken together with the nitrogen atom to which they are        bound, form an optionally substituted group selected from        3-6-membered heterocyclyl having 1-5 heteroatoms independently        selected from nitrogen, oxygen, or sulfur, or 5-10-membered        heteroaryl having 1-5 heteroatoms independently selected from        nitrogen, oxygen, or sulfur;

G₁ is N or —CR⁸, wherein R⁸ is H, CN, halogen, —Z₂—R⁹, C₁₋₆ aliphatic,or 3-10-membered cycloaliphatic, wherein:

-   -   Z₂ is selected from an optionally substituted C₁₋₃ alkylene        chain, —O—, —N(R^(8a))—, —S—, —S(O)—, S(O)₂—, —C(O)—, —CO₂—,        —C(O)NR^(8a)—, —N(R^(8a))C(O)—, —N(R^(8a))CO₂—, —S(O)₂NR^(8a)—,        —N(R^(8a))S(O)₂—, —OC(O)N(R^(8a))—, —N(R^(8a))C(O)NR^(8a)—,        —N(R^(8a))S(O)₂N(R^(8a))—, or —OC(O)—;        -   R^(8a) is hydrogen or an optionally substituted C₁₋₄            aliphatic, and    -   R⁹ is hydrogen or an optionally substituted group selected from        C₁₋₆ aliphatic, 3-10-membered cycloaliphatic, 4-10-membered        heterocyclyl having 1-5 heteroatoms independently selected from        nitrogen, oxygen, or sulfur, 6-10-membered aryl, or        5-10-membered heteroaryl having 1-5 heteroatoms independently        selected from nitrogen, oxygen, or sulfur; and

HY is an optionally substituted group selected from:

wherein each occurrence of X₄, X₅, X₆, and X₇ is independently —CR¹⁰ orN, provided no more than two occurrences of X₄, X₅, X₆, and X₇ are N;

each occurrence of Q₁ and Q₂ is independently S, O or —NR⁵;

each occurrence of Y₁, Y₂, Y₃, Y₄, Y₅, Y₆, Y₇, Y₈, and Y₉ isindependently —CR¹⁰ or N, provided no more than two occurrences of Y₆,Y₇, Y₈, and Y₉ are N;

-   -   or wherein two adjacent occurrences of X₄ and X₅, X₆ and X₇, Y₁        and Q₁, Y₃ and Q₂, or Y₄ and Y₅ taken together with the atom to        which they are bound, form an optionally substituted fused group        selected from 5-6-membered aryl, or 5-6-membered heteroaryl        having 1-5 heteroatoms independently selected from nitrogen,        oxygen, or sulfur;        wherein R¹⁰ is —R^(10b), —V₁—R^(10c), -T₁-R^(10b), or        —V₁-T₁-R^(10b) wherein:    -   V₁ is —NR¹¹—, —NR¹¹—C(O)—, —NR¹¹—C(S)—, —NR¹¹—C(NR¹¹)—,        —NR¹¹C(O)OR^(10a)—, —NR¹¹C(O)NR¹¹—, —NR¹¹C(O)SR^(10a)—,        —NR¹¹C(S)OR^(10a)—, —NR¹¹C(S)NR¹¹—, —NR¹¹C(S)SR^(10a)—,        —NR¹¹C(NR¹¹)OR^(10a)—, —NR¹¹C(NR¹¹)NR¹¹—, —NR¹¹S(O)₂—,        —NR¹¹S(O)₂NR¹¹—, —C(O)—, —CO₂—, —C(O)NR¹¹—, —C(O)NR¹¹O—, —SO₂—,        or —SO₂NR¹¹—;    -   each occurrence of R^(10a) is independently hydrogen or an        optionally substituted group selected from C₁₋₆ aliphatic,        3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having        1-5 heteroatoms independently selected from nitrogen, oxygen, or        sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having        1-5 heteroatoms independently selected from nitrogen, oxygen, or        sulfur;    -   T₁ is an optionally substituted C₁-C₆ alkylene chain wherein the        alkylene chain optionally is interrupted by —N(R¹¹)—, —O—, —S—,        —S(O)—, —S(O)₂—, —C(O)—, —C(O)O—, —C(O)N(R¹¹)—, —S(O)₂N(R¹¹)—,        —OC(O)N(R¹¹)—, —N(R¹¹)C(O)—, —N(R¹¹)SO₂—, —N(R^(11a))C(O)—,        —NR^(10a)C(O)N(R^(10a))—, —N(R^(10a))S(O)₂N(R^(10a))—, —OC(O)—,        or —C(O)N(R¹¹)—O— or wherein T₁ forms part of an optionally        substituted 3-7 membered cycloaliphatic or heterocyclyl ring;    -   each occurrence of R^(10b) is independently hydrogen, halogen,        —CN, —NO₂, —N(R¹¹)₂, —OR^(10a), —SR^(10a), —S(O)₂R^(10a),        —C(O)R^(10a), —C(O)OR^(10a), —C(O)N(R¹¹)₂, —S(O)₂N(R¹¹)₂,        —OC(O)N(R¹¹)₂, —N(R¹¹)C(O)R^(10a), —N(R¹¹)SO₂R^(10a),        —N(R¹¹)C(O)OR^(10a), —N(R¹¹)C(O)N(R¹¹)₂, or N(R¹¹)SO₂N(R¹¹)₂, or        an optionally substituted group selected from C₁₋₆ aliphatic,        3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having        1-5 heteroatoms independently selected from nitrogen, oxygen, or        sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having        1-5 heteroatoms independently selected from nitrogen, oxygen, or        sulfur;    -   each occurrence of R^(10c) is independently hydrogen or an        optionally substituted group selected from C₁₋₆ aliphatic,        3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having        1-5 heteroatoms independently selected from nitrogen, oxygen, or        sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having        1-5 heteroatoms independently selected from nitrogen, oxygen, or        sulfur, or    -   R^(10a) and R^(10c) taken together with a nitrogen atom to which        they are bound form an optionally substituted 4-7-membered        heterocyclyl ring having 0-1 additional heteroatoms        independently selected from nitrogen, oxygen, or sulfur;

each occurrence of R¹¹ is independently hydrogen, —C(O)R^(11a),—CO₂R^(11a), —C(O)N(R^(11a))₂, —C(O)N(R^(11a))—OR^(11a), —SO₂R^(11a),—SO₂N(R^(11a))₂, or an optionally substituted group selected from C₁₋₆aliphatic, 3-10-membered cycloaliphatic, 4-10-membered heterocyclylhaving 1-5 heteroatoms independently selected from nitrogen, oxygen, orsulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5heteroatoms independently selected from nitrogen, oxygen, or sulfur;

-   -   wherein each occurrence of R^(11a) is independently hydrogen or        an optionally substituted group selected from C₁₋₆aliphatic,        3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having        1-5 heteroatoms independently selected from nitrogen, oxygen, or        sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having        1-5 heteroatoms independently selected from nitrogen, oxygen, or        sulfur;

each occurrence of R⁵ is independently hydrogen, —C(O)R^(5a),—CO₂R^(5a), —C(O)N(R^(5b))₂, —SO₂R^(5a), —SO₂N(R^(5b))₂, or anoptionally substituted group selected from C₁₋₆ aliphatic, 3-10-memberedcycloaliphatic, 4-10-membered heterocyclyl having 1-5 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, 6-10-memberedaryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur;

-   -   wherein each occurrence of R^(5a) is independently hydrogen or        an optionally substituted group selected from C₁₋₆ aliphatic,        3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having        1-5 heteroatoms independently selected from nitrogen, oxygen, or        sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having        1-5 heteroatoms independently selected from nitrogen, oxygen, or        sulfur;        wherein each occurrence of R^(5b) is independently hydrogen or        an optionally substituted group selected from C₁₋₆ aliphatic,        3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having        1-5 heteroatoms independently selected from nitrogen, oxygen, or        sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having        1-5 heteroatoms independently selected from nitrogen, oxygen, or        sulfur; or two occurrences of R^(5b) taken together with the        nitrogen atom to which they are bound, form an optionally        substituted group selected from 3-6-membered heterocyclyl having        1-5 heteroatoms independently selected from nitrogen, oxygen, or        sulfur, or 5-10-membered heteroaryl having 1-5 heteroatoms        independently selected from nitrogen, oxygen, or sulfur,        provided that:        a) for compounds of formula IB-a compounds are other than:

and

-   -   when G¹ is CR⁸, R¹ is CONH₂, and W is NH, then HY is other than

andb) the compound is other than:

In another embodiment, the compounds of this invention are representedby formula IA or IB:

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is CY, —C(O)N(R³)₂, —C(O)OR³, —C(O)(NH)OH, —C(═NH)NHOH,—C(O)NR³N(R³)₂, —C(═N—NH₂)NH₂, —C(═N)N(R³)₂, wherein:

-   -   CY is an optionally substituted group selected from:

wherein:

-   -   G₂ is —N═, ═N—, or —N(R^(3′))—, wherein:    -   each occurrence of R³ and R^(3′) is independently hydrogen or an        optionally substituted C₁₋₆ aliphatic, wherein:    -   X₁, X₂, and X₃, are each independently N, NR^(3′), O, S, or CR⁴,        provided that only one of X₁, X₂, or X₃ may be O, S, or NR^(3′);    -   X₈, X₉, X₁₀, and X₁₁ are each independently N, or CR⁴, provided        no more than two occurrences of X₈, X₉, X₁₀, and X₁₁ are N;    -   each occurrence of R⁴ is independently hydrogen, —CN, halogen,        —Z₃—R⁶, or an optionally substituted group selected from C₁₋₆        aliphatic, or 3-10-membered cycloaliphatic,    -   wherein:        -   Z₃ is selected from an optionally substituted C₁₋₃ alkylene            chain, —O—, —N(R^(4a))—, —S—, —S(O)—, —S(O)₂—, —C(O)—,            —CO₂—, —C(O)NR^(4a)—, —N(R^(4a))C(O)—, —N(R^(4a))CO₂—,            —S(O)₂NR^(4a)—, —N(R^(4a))S(O)₂—, —OC(O)N(R^(4a))—,            —N(R^(4a))C(O)NR^(4a)—, —N(R^(4a))S(O)₂N(R^(4a))—, or            —OC(O)—;        -   R^(4a) is hydrogen or an optionally substituted C₁₋₄            aliphatic, and        -   R⁶ is hydrogen or an optionally substituted group selected            from C₁₋₆ aliphatic, 3-10-membered cycloaliphatic,            4-10-membered heterocyclyl having 1-5 heteroatoms            independently selected from nitrogen, oxygen, or sulfur,            6-10-membered aryl, or 5-10-membered heteroaryl having 1-5            heteroatoms independently selected from nitrogen, oxygen, or            sulfur;        -   or wherein two adjacent occurrences of R^(3′) or R⁴, taken            together with the atom to which they are bound, form an            optionally substituted fused group selected from            5-6-membered aryl, or 5-6-membered heteroaryl having 1-5            heteroatoms independently selected from nitrogen, oxygen, or            sulfur;    -   Y₁₀ is —OR^(4′) or —N(R^(4′))₂;    -   Y₁₁ is O or N—R^(4′);    -   each occurrence of R^(4′) is independently hydrogen or an        optionally substituted C₁₋₆ aliphatic;

Ring A is a group selected from 3-10-membered cycloaliphatic,4-10-membered heterocyclyl having 1-5 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-memberedheteroaryl having 1-5 heteroatoms independently selected from nitrogen,oxygen, or sulfur;

each occurrence of R² is independently —R^(12a), -T₂-R^(12d), orV₂-T₂-R^(12d), and:

-   -   each occurrence of R^(12a) is independently halogen, —CN, —NO₂,        —R^(12c), —N(R^(12b))₂, —OR^(12b), —SR^(12c), —S(O)₂R^(12c),        —C(O)R^(12b), —C(O)OR^(12b), —C(O)N(R^(12b))₂,        —S(O)₂N(R^(12b))₂, —OC(O)N(R^(12b))₂, —N(R^(12e))C(O)R^(12b),        —N(R^(12e))SO₂R^(12c), —N(R^(12e))C(O)OR^(12b),        —N(R^(12e))C(O)N(R^(12b))₂, or N(R^(12e))SO₂N(R^(12b))₂, or two        occurrences of R^(12b), taken together with a nitrogen atom to        which they are bound, form an optionally substituted        4-7-membered heterocyclyl ring having 0-1 additional heteroatoms        selected from nitrogen, oxygen, or sulfur;    -   each occurrence of R^(12b) is independently hydrogen or an        optionally substituted group selected from C₁-C₆ aliphatic,        3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having        1-5 heteroatoms independently selected from nitrogen, oxygen, or        sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having        1-5 heteroatoms independently selected from nitrogen, oxygen, or        sulfur;    -   each occurrence of R^(12C) is independently an optionally        substituted group selected from C₁-C₆ aliphatic, 3-10-membered        cycloaliphatic, 4-10-membered heterocyclyl having 1-5        heteroatoms independently selected from nitrogen, oxygen, or        sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having        1-5 heteroatoms independently selected from nitrogen, oxygen, or        sulfur;    -   each occurrence of R^(12d) is independently hydrogen or an        optionally substituted from 3-10-membered cycloaliphatic,        4-10-membered heterocyclyl having 1-5 heteroatoms independently        selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl,        or 5-10-membered heteroaryl having 1-5 heteroatoms independently        selected from nitrogen, oxygen, or sulfur;    -   each occurrence of R^(12e) is independently hydrogen or an        optionally substituted C₁₋₆ aliphatic group;    -   each occurrence of V₂ is independently —N(R^(12e))—, —O—, —S—,        —S(O)—, —S(O)₂—, —C(O)—, —C(O)O—, —C(O)N(R^(12e))—,        —S(O)₂N(R^(12e))—, —OC(O)N(R^(12e))—, —N(R^(12e))C(O)—,        —N(R^(12e))SO₂—, —N(R^(12e))C(O)O—, —N(R^(12e))C(O)N(R^(12e))—,        —N(R^(12e))SO₂N(R^(12e))—, —OC(O)—, or —C(O)N(R^(12e))—O—; and

T₂ is an optionally substituted C₁-C₆ alkylene chain wherein thealkylene chain optionally is interrupted by —N(R¹³)—, —O—, —S—, —S(O)—,—S(O)₂—, —C(O)—, —C(O)O—, —C(O)N(R¹³)—, —S(O)₂N(R¹³)—, —OC(O)N(R¹³)—,—N(R¹³)C(O)—, —N(R¹³)SO₂—, —N(R¹³)C(O)O—, —N(R¹³)C(O)N(R¹³)—,—N(R¹³)S(O)₂N(R¹³)—, —OC(O)—, or —C(O)N(R¹³)—O— or wherein T₂ or aportion thereof optionally forms part of an optionally substituted 3-7membered cycloaliphatic or heterocyclyl ring, wherein R¹³ is hydrogen oran optionally substituted C₁₋₄aliphatic group;

n is 0 to 4;

W is selected from —C(R⁷)₂—, —C(═C(R⁷)₂)—, —C(R⁷)₂O—, —C(R⁷)₂NR^(7a)—,—O—, —N(R^(7b))—, —S—, —S(O)—, —S(O)₂—, —C(O)—, —C(O)NR^(7a)—, or—N(R^(7a))C(O)—, wherein:

-   -   each occurrence of R⁷ is independently hydrogen, or an        optionally substituted group selected from C₁₋₆ aliphatic,        6-10-membered aryl, 5-10-membered heteroaryl having 1-5        heteroatoms independently selected from nitrogen, oxygen, or        sulfur, —N(R^(7b))₂, —OR^(7a), —SR^(7a), halo, or —CN;    -   each occurrence of R^(7a) is independently hydrogen or        optionally substituted C₁₋₆ aliphatic or optionally substituted        C₃₋₆ cycloaliphatic;    -   each occurrence of R^(7b) is independently hydrogen, optionally        substituted C₁₋₆ aliphatic, optionally substituted C₃₋₆        cycloaliphatic, —C(O)R^(7a), —C(O)OR^(7a), S(O)R^(7a), or        —S(O)₂R^(7a); or    -   wherein any two occurrences of R⁷, R^(7a), or R^(7b) taken        together with the atom to which they are bound, form an        optionally substituted group selected from a 3-6-membered        cycloaliphatic ring, 6-10-membered aryl, 3-6-membered        heterocyclyl having 1-5 heteroatoms independently selected from        nitrogen, oxygen, or sulfur, or 5-10-membered heteroaryl having        1-5 heteroatoms independently selected from nitrogen, oxygen, or        sulfur;    -   or wherein any two occurrences of R^(7a) and R², or R^(7b) and        R² taken together with the nitrogen atom to which they are        bound, form an optionally substituted group selected from        3-6-membered heterocyclyl having 1-5 heteroatoms independently        selected from nitrogen, oxygen, or sulfur, or 5-10-membered        heteroaryl having 1-5 heteroatoms independently selected from        nitrogen, oxygen, or sulfur;

G₁ is N or —CR⁸, wherein R⁸ is H, —CN, halogen, —Z₂—R⁹, C₁₋₆ aliphatic,or 3-10-membered cycloaliphatic, wherein:

-   -   Z₂ is selected from an optionally substituted C₁₋₃ alkylene        chain, —O—, —N(R^(8a))—, —S—, —S(O)—, S(O)₂—, —C(O)—, —CO₂—,        —C(O)NR^(8a)—, —N(R^(8a))C(O)—, —N(R^(8a))CO₂—, —S(O)₂NR^(8a)—,        —N(R^(8a))S(O)₂—, —OC(O)N(R^(8a))—, —N(R^(8a))C(O)NR^(8a)—,        —N(R^(8a))S(O)₂N(R^(8a))—, or —OC(O)—;        -   R^(8a) is hydrogen or an optionally substituted C₁₋₄            aliphatic, and    -   R⁹ is hydrogen or an optionally substituted group selected from        C₁₋₆ aliphatic, 3-10-membered cycloaliphatic, 4-10-membered        heterocyclyl having 1-5 heteroatoms independently selected from        nitrogen, oxygen, or sulfur, 6-10-membered aryl, or        5-10-membered heteroaryl having 1-5 heteroatoms independently        selected from nitrogen, oxygen, or sulfur; and HY is an        optionally substituted group selected from:

wherein each occurrence of X₄, X₅, X₆, and X₇ is independently —CR¹⁰ orN, provided no more than two occurrences of X₄, X₅, X₆, and X₇ are N;

each occurrence of Q₁ and Q₂ is independently S, O or —NR⁵;

each occurrence of Y₁, Y₂, Y₃, Y₄, Y₅, Y₆, Y₇, Y₈, and Y₉ isindependently —CR¹⁰ or N, provided no more than two occurrences of Y₆,Y₇, Y₈, and Y₉ are N;

-   -   or wherein two adjacent occurrences of X₄ and X₅, X₆ and X₇, Y₁        and Q₁, Y₃ and Q₂, or Y₄ and Y₅ taken together with the atom to        which they are bound, form an optionally substituted fused group        selected from 5-6-membered aryl, or 5-6-membered heteroaryl        having 1-5 heteroatoms independently selected from nitrogen,        oxygen, or sulfur;        wherein R¹⁰ is —R^(10b), —V₁—R^(10c), -T₁-R^(10b), or        —V₁-T₁-R^(10b) wherein:    -   V₁ is —NR¹¹—, —NR¹¹—C(O)—, —NR¹¹—C(S)—, —NR¹¹—C(NR¹¹)—,        —NR¹¹C(O)OR^(10a)—, —NR¹¹C(O)NR¹¹—, —NR¹¹C(O)SR^(10a)—,        —NR¹¹C(S)OR^(10a)—, —NR¹¹C(S)NR¹¹—, —NR¹¹C(S)SR^(10a)—,        —NR¹¹C(NR¹¹)OR^(10a)—, —NR¹¹C(NR¹¹)NR¹¹—, —NR¹¹S(O)₂—,        —NR¹¹S(O)₂NR¹¹—, —C(O)—, —CO₂—, —C(O)NR¹¹—, —C(O)NR¹¹O—, —SO₂—,        or —SO₂NR¹¹—;    -   each occurrence of R^(10a) is independently hydrogen or an        optionally substituted group selected from C₁₋₆ aliphatic,        3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having        1-5 heteroatoms independently selected from nitrogen, oxygen, or        sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having        1-5 heteroatoms independently selected from nitrogen, oxygen, or        sulfur;    -   T₁ is an optionally substituted C₁-C₆ alkylene chain wherein the        alkylene chain optionally is interrupted by —N(R¹¹)—, —O—, —S—,        —S(O)—, —S(O)₂—, —C(O)—, —C(O)O—, —C(O)N(R¹¹)—, —S(O)₂N(R¹¹)—,        —OC(O)N(R¹¹)—, —N(R¹¹)C(O)—, —N(R¹¹)SO₂—, —N(R^(11a))C(O)O—,        —NR^(10a)C(O)N(R^(10a))—, —N(R^(10a))S(O)₂N(R^(10a))—, —OC(O)—,        or —C(O)N(R¹¹)—O— or wherein T₁ forms part of an optionally        substituted 3-7 membered cycloaliphatic or heterocyclyl ring;    -   each occurrence of R^(lob) is independently hydrogen, halogen,        —CN, —NO₂, —N(R¹¹)₂, —OR^(10a), —SR^(10a), —S(O)₂R^(10a),        —C(O)R^(10a), —C(O)OR^(10a), —C(O)N(R¹¹)₂, —S(O)₂N(R¹¹)₂,        —OC(O)N(R¹¹)₂, —N(R¹¹)C(O)R^(10a), —N(R¹¹)SO₂R^(10a),        —N(R¹¹)C(O)OR^(10a), —N(R¹¹)C(O)N(R¹¹)₂, or —N(R¹¹)SO₂N(R¹¹)₂,        or an optionally substituted group selected from C₁₋₆ aliphatic,        3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having        1-5 heteroatoms independently selected from nitrogen, oxygen, or        sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having        1-5 heteroatoms independently selected from nitrogen, oxygen, or        sulfur;    -   each occurrence of R^(10c) is independently hydrogen or an        optionally substituted group selected from C₁₋₆ aliphatic,        3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having        1-5 heteroatoms independently selected from nitrogen, oxygen, or        sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having        1-5 heteroatoms independently selected from nitrogen, oxygen, or        sulfur, or    -   R^(10a) and R^(10c) taken together with a nitrogen atom to which        they are bound form an optionally substituted 4-7-membered        heterocyclyl ring having 0-1 additional heteroatoms        independently selected from nitrogen, oxygen, or sulfur;

each occurrence of R¹¹ is independently hydrogen, —C(O)R^(11a),—CO₂R^(11a), —C(O)N(R^(11a))₂, —C(O)N(R^(11a))—OR^(11a), —SO₂R^(11a),—SO₂N(R^(11a))₂, or an optionally substituted group selected from C₁₋₆aliphatic, 3-10-membered cycloaliphatic, 4-10-membered heterocyclylhaving 1-5 heteroatoms independently selected from nitrogen, oxygen, orsulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5heteroatoms independently selected from nitrogen, oxygen, or sulfur;

-   -   wherein each occurrence of R^(11a) is independently hydrogen or        an optionally substituted group selected from C₁₋₆aliphatic,        3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having        1-5 heteroatoms independently selected from nitrogen, oxygen, or        sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having        1-5 heteroatoms independently selected from nitrogen, oxygen, or        sulfur;

each occurrence of R⁵ is independently hydrogen, —C(O)R^(5a),—CO₂R^(5a), —C(O)N(R^(5b))₂, —SO₂R^(5a), —SO₂N(R^(5b))₂, or anoptionally substituted group selected from C₁₋₆ aliphatic, 3-10-memberedcycloaliphatic, 4-10-membered heterocyclyl having 1-5 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, 6-10-memberedaryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur;

-   -   wherein each occurrence of R^(5a) is independently hydrogen or        an optionally substituted group selected from C₁₋₆ aliphatic,        3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having        1-5 heteroatoms independently selected from nitrogen, oxygen, or        sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having        1-5 heteroatoms independently selected from nitrogen, oxygen, or        sulfur;    -   wherein each occurrence of R^(5b) is independently hydrogen or        an optionally substituted group selected from C₁₋₆ aliphatic,        3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having        1-5 heteroatoms independently selected from nitrogen, oxygen, or        sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having        1-5 heteroatoms independently selected from nitrogen, oxygen, or        sulfur; or two occurrences of R^(5b) taken together with the        nitrogen atom to which they are bound, form an optionally        substituted group selected from 3-6-membered heterocyclyl having        1-5 heteroatoms independently selected from nitrogen, oxygen, or        sulfur, or 5-10-membered heteroaryl having 1-5 heteroatoms        independently selected from nitrogen, oxygen, or sulfur;        provided that:        a) for compounds of formula IB compounds are other than:

and

-   -   when G¹ is CR⁸, R¹ is CONH₂, and W is NH, then HY is other than

andb) the compound is other than:

In another aspect, the compounds of this invention are represented byformula IA or IB:

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is CY, —C(O)N(R³)₂, —C(O)OR³, —C(O)(NH)OH, —C(═NH)NHOH,—C(O)NR³N(R³)₂, —C(═N—NH₂)NH₂, —C(═N)N(R³)₂, wherein:

-   -   CY is

wherein:

-   -   G₂ is —N═, ═N—, or —N(R^(3′)), wherein:    -   each occurrence of R³ and R^(3′) is independently hydrogen or an        optionally substituted C₁₋₆ aliphatic, wherein:    -   X₁, X₂, and X₃, are each independently N, NR^(3′), O, S, or CR⁴,        provided that only one of X₁, X₂, or X₃ may be O, S, or NR^(3′);        -   each occurrence of R⁴ is independently hydrogen, —CN,            halogen, —Z₃—R⁶, or an optionally substituted group selected            from C₁₋₆ aliphatic, or 3-10-membered cycloaliphatic,            wherein:        -   Z₃ is selected from an optionally substituted C₁₋₃ alkylene            chain, —O—, —N(R^(4a))—, —S—, —S(O)—, —S(O)₂—, —C(O)—,            —CO₂—, —C(O)NR^(4a)—, —N(R^(4a))C(O)—, —N(R^(4a))CO₂—,            —S(O)₂NR^(4a)—, —N(R^(4a))S(O)₂—, —OC(O)N(R^(4a))—,            —N(R^(4a))C(O)NR^(4a)—, —N(R^(4a))S(O)₂N(R^(4a))—, or            —OC(O)—;        -   R^(4a) is hydrogen or an optionally substituted C₁₋₄            aliphatic, and        -   R⁶ is hydrogen or an optionally substituted group selected            from C₁₋₆ aliphatic, 3-10-membered cycloaliphatic,            4-10-membered heterocyclyl having 1-5 heteroatoms            independently selected from nitrogen, oxygen, or sulfur,            6-10-membered aryl, or 5-10-membered heteroaryl having 1-5            heteroatoms independently selected from nitrogen, oxygen, or            sulfur;        -   or wherein two adjacent occurrences of R^(3′) or R⁴, taken            together with the atom to which they are bound, form an            optionally substituted fused group selected from            5-6-membered aryl, or 5-6-membered heteroaryl having 1-5            heteroatoms independently selected from nitrogen, oxygen, or            sulfur;

Ring A is a group selected from 3-10-membered cycloaliphatic,4-10-membered heterocyclyl having 1-5 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-memberedheteroaryl having 1-5 heteroatoms independently selected from nitrogen,oxygen, or sulfur;

each occurrence of R² is independently —R^(12a), -T₂-R^(12d), or—V₂-T₂-R^(12d), and:

-   -   each occurrence of R^(12a) is independently halogen, —CN, —NO₂,        —R^(12c), —N(R^(12b))₂, —OR^(12b), —SR^(12c), —S(O)₂R^(12c),        —C(O)R^(12b), —C(O)OR^(12b), —C(O)N(R^(12b))₂,        —S(O)₂N(R^(12b))₂, —OC(O)N(R^(12b))₂, —N(R^(12e))C(O)R^(12b),        —N(R^(12e))SO₂R^(12c), —N(R^(12e))C(O)OR^(12b),        —N(R^(12e))C(O)N(R^(12b))₂, or —N(R^(12e))SO₂N(R^(12b))₂, or two        occurrences of R^(12b), taken together with a nitrogen atom to        which they are bound, form an optionally substituted        4-7-membered heterocyclyl ring having 0-1 additional heteroatoms        selected from nitrogen, oxygen, or sulfur;    -   each occurrence of R^(12b) is independently hydrogen or an        optionally substituted group selected from C₁-C₆ aliphatic,        3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having        1-5 heteroatoms independently selected from nitrogen, oxygen, or        sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having        1-5 heteroatoms independently selected from nitrogen, oxygen, or        sulfur;    -   each occurrence of R^(12c) is independently an optionally        substituted group selected from C₁-C₆ aliphatic, 3-10-membered        cycloaliphatic, 4-10-membered heterocyclyl having 1-5        heteroatoms independently selected from nitrogen, oxygen, or        sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having        1-5 heteroatoms independently selected from nitrogen, oxygen, or        sulfur;    -   each occurrence of R^(12d) is independently hydrogen or an        optionally substituted from 3-10-membered cycloaliphatic,        4-10-membered heterocyclyl having 1-5 heteroatoms independently        selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl,        or 5-10-membered heteroaryl having 1-5 heteroatoms independently        selected from nitrogen, oxygen, or sulfur;    -   each occurrence of R^(12e) is independently hydrogen or an        optionally substituted C₁₋₆ aliphatic group;    -   each occurrence of V₂ is independently —N(R^(12e))—, —O—, —S—,        —S(O)—, —S(O)₂—, —C(O)—, —C(O)O—, —C(O)N(R^(12e))—,        —S(O)₂N(R^(12e))—, —OC(O)N(R^(12e))—, —N(R^(12e))C(O)—,        —N(R^(12e))SO₂—, —N(R^(12e))C(O)O—, —N(R^(12e))C(O)N(R^(12e))—,        —N(R^(12e))SO₂N(R^(12e))—, —OC(O)—, or —C(O)N(R^(12e))—O—; and

T₂ is an optionally substituted C₁-C₆ alkylene chain wherein thealkylene chain optionally is interrupted

by —N(R¹³)—, —O—, —S—, —S(O)—, —S(O)₂—, —C(O)—, —C(O)O—, —C(O)N(R¹³)—,—S(O)₂N(R¹³)—, —OC(O)N(R¹³)—, —N(R¹³)C(O)—, —N(R¹³)SO₂—, —N(R¹³)C(O)O—,—N(R¹³)C(O)N(R¹³)—, —N(R¹³)S(O)₂N(R¹³)—, —OC(O)—, or —C(O)N(R¹³)—O— orwherein T₂ or a portion thereof optionally forms part of an optionallysubstituted 3-7 membered cycloaliphatic or heterocyclyl ring, whereinR¹³ is hydrogen or an optionally substituted C₁₋₄aliphatic group;

n is 0 to 4;

W is selected from —C(R⁷)₂—, —C(═C(R⁷)₂)—, —C(R⁷)₂O—, —C(R⁷)₂NR^(7a)—,—O—, —N(R^(7b))—, —S—, —S(O)—, —S(O)₂—, —C(O)—, —C(O)NR^(7a)—, or—N(R^(7a))C(O)—, wherein:

-   -   each occurrence of R⁷ is independently hydrogen, or an        optionally substituted group selected from C₁₋₆ aliphatic,        6-10-membered aryl, 5-10-membered heteroaryl having 1-5        heteroatoms independently selected from nitrogen, oxygen, or        sulfur, —N(R^(7b))₂, —OR^(7a), —SR^(7a), halo, or —CN;    -   each occurrence of R^(7a) is independently hydrogen or        optionally substituted C₁₋₆ aliphatic or optionally substituted        C₃₋₆ cycloaliphatic;    -   each occurrence of R^(7b) is independently hydrogen, optionally        substituted C₁₋₆ aliphatic, optionally substituted C₃₋₆        cycloaliphatic, —C(O)R^(7a), —C(O)OR^(7a), S(O)R^(7a), or        —S(O)₂R^(7a); or    -   wherein any two occurrences of R⁷, R^(7a), or R^(7b) taken        together with the atom to which they are bound, form an        optionally substituted group selected from a 3-6-membered        cycloaliphatic ring, 6-10-membered aryl, 3-6-membered        heterocyclyl having 1-5 heteroatoms independently selected from        nitrogen, oxygen, or sulfur, or 5-10-membered heteroaryl having        1-5 heteroatoms independently selected from nitrogen, oxygen, or        sulfur;    -   or wherein any two occurrences of R^(7a) and R², or R^(7b) and        R² taken together with the nitrogen atom to which they are        bound, form an optionally substituted group selected from        3-6-membered heterocyclyl having 1-5 heteroatoms independently        selected from nitrogen, oxygen, or sulfur, or 5-10-membered        heteroaryl having 1-5 heteroatoms independently selected from        nitrogen, oxygen, or sulfur;

G₁ is N or —CR⁸, wherein R⁸ is H, —CN, halogen, —Z₂—R⁹, C₁₋₆ aliphatic,or 3-10-membered cycloaliphatic, wherein:

-   -   Z₂ is selected from an optionally substituted C₁₋₃ alkylene        chain, —O—, —N(R^(8a))—, —S—, —S(O)—, S(O)₂—, —C(O)—, —CO₂—,        —C(O)NR^(8a)—, —N(R^(8a))C(O)—, —N(R^(8a))CO₂—, —S(O)₂NR^(8a)—,        —N(R^(8a))S(O)₂—, —OC(O)N(R^(8a))—, —N(R^(8a))C(O)NR^(8a)—,        —N(R^(8a))S(O)₂N(R^(8a))—, or —OC(O)—;        -   R^(8a) is hydrogen or an optionally substituted C₁₋₄            aliphatic, and    -   R⁹ is hydrogen or an optionally substituted group selected from        C₁₋₆ aliphatic, 3-10-membered cycloaliphatic, 4-10-membered        heterocyclyl having 1-5 heteroatoms independently selected from        nitrogen, oxygen, or sulfur, 6-10-membered aryl, or        5-10-membered heteroaryl having 1-5 heteroatoms independently        selected from nitrogen, oxygen, or sulfur; and HY is an        optionally substituted group selected from:

wherein each occurrence of X₄, X₅, X₆, and X₇ is independently —CR¹⁰ orN, provided no more than two occurrences of X₄, X₅, X₆, and X₇ are N;

each occurrence of Q₁ and Q₂ is independently S, O or —NR⁵;

each occurrence of Y₁, Y₂, Y₃, Y₄, Y₅, Y₆, Y₇, Y₈, and Y₉ isindependently —CR¹⁰ or N, provided no more than two occurrences of Y₆,Y₇, Y₈, and Y₉ are N;

-   -   or wherein two adjacent occurrences of X₄ and X₅, X₆ and X₇, Y₁        and Q₁, Y₃ and Q₂, or Y₄ and Y₅ taken together with the atom to        which they are bound, form an optionally substituted fused group        selected from 5-6-membered aryl, or 5-6-membered heteroaryl        having 1-5 heteroatoms independently selected from nitrogen,        oxygen, or sulfur;        wherein R¹⁰ is R^(10b), —V₁R^(10c), -T₁-R^(10b), or        —V₁-T₁-R^(10b) wherein:    -   V₁ is —NR¹¹—, —NR¹¹—C(O)—, —NR¹¹—C(S)—, —NR¹¹—C(NR¹¹)—,        —NR¹¹C(O)OR^(10a)—, —NR¹¹C(O)NR¹¹—, —NR¹¹C(O)SR^(10a)—,        —NR¹¹C(S)OR^(10a)—, —NR¹¹C(S)NR¹¹—, —NR¹¹C(S)SR^(10a)—,        —NR¹¹C(NR¹¹)OR^(10a)—, —NR¹¹C(NR¹¹)NR¹¹—, —NR¹¹S(O)₂—,        —NR¹¹S(O)₂NR¹¹—, —C(O)—, —CO₂—, —C(O)NR¹¹—, —C(O)NR¹¹O—, —SO₂—,        or —SO₂NR¹¹—;    -   each occurrence of R^(10′) is independently hydrogen or an        optionally substituted group selected from C₁₋₆ aliphatic,        3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having        1-5 heteroatoms independently selected from nitrogen, oxygen, or        sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having        1-5 heteroatoms independently selected from nitrogen, oxygen, or        sulfur;    -   T₁ is an optionally substituted C₁-C₆ alkylene chain wherein the        alkylene chain optionally is interrupted by —N(R¹¹)—, —O—, —S—,        —S(O)—, —S(O)₂—, —C(O)—, —C(O)O—, —C(O)N(R¹¹)—, —S(O)₂N(R¹¹)—,        —OC(O)N(R¹¹)—, —N(R¹¹)C(O)—, —N(R¹¹)SO₂—, —N(R^(11a))C(O)O—,        —NR^(10a)C(O)N(R^(10a))—, —N(R^(10a))S(O)₂N(R^(10a))—, —OC(O)—,        or —C(O)N(R¹¹)—O— or wherein T₁ forms part of an optionally        substituted 3-7 membered cycloaliphatic or heterocyclyl ring;    -   each occurrence of R^(10b) is independently hydrogen, halogen,        —CN, —NO₂, —N(R¹¹)₂, —OR^(10a), —SR^(10a), —S(O)₂R^(10a),        —C(O)R^(10a), —C(O)OR^(10a), —C(O)N(R¹¹)₂, —S(O)₂N(R¹¹)₂,        —OC(O)N(R¹¹)₂, —N(R¹¹)C(O)R^(11a), —N(R¹¹)SO₂R^(10a),        —N(R¹¹)C(O)OR^(10a), —N(R¹¹)C(O)N(R¹¹)₂, or —N(R¹¹)SO₂N(R¹¹)₂,        or an optionally substituted group selected from C₁₋₆ aliphatic,        3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having        1-5 heteroatoms independently selected from nitrogen, oxygen, or        sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having        1-5 heteroatoms independently selected from nitrogen, oxygen, or        sulfur;    -   each occurrence of R^(10c) is independently hydrogen or an        optionally substituted group selected from C₁₋₆ aliphatic,        3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having        1-5 heteroatoms independently selected from nitrogen, oxygen, or        sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having        1-5 heteroatoms independently selected from nitrogen, oxygen, or        sulfur, or    -   R^(10a) and R^(10c) taken together with a nitrogen atom to which        they are bound form an optionally substituted 4-7-membered        heterocyclyl ring having 0-1 additional heteroatoms        independently selected from nitrogen, oxygen, or sulfur;

each occurrence of R¹¹ is independently hydrogen, —C(O)R^(11a),—CO₂R^(11a), —C(O)N(R^(11a))₂, —C(O)N(R^(11a))—OR^(11a), —SO₂R^(11a),—SO₂N(R^(11a))₂, or an optionally substituted group selected from C₁₋₆aliphatic, 3-10-membered cycloaliphatic, 4-10-membered heterocyclylhaving 1-5 heteroatoms independently selected from nitrogen, oxygen, orsulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5heteroatoms independently selected from nitrogen, oxygen, or sulfur;

-   -   wherein each occurrence of R^(11a) is independently hydrogen or        an optionally substituted group selected from C₁₋₆aliphatic,        3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having        1-5 heteroatoms independently selected from nitrogen, oxygen, or        sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having        1-5 heteroatoms independently selected from nitrogen, oxygen, or        sulfur;

each occurrence of R⁵ is independently hydrogen, —C(O)R^(5a),—CO₂R^(5a), —C(O)N(R^(5b))₂, —SO₂R^(5a), —SO₂N(R^(5b))₂, or anoptionally substituted group selected from C₁₋₆ aliphatic, 3-10-memberedcycloaliphatic, 4-10-membered heterocyclyl having 1-5 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, 6-10-memberedaryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur;

-   -   wherein each occurrence of Rya is independently hydrogen or an        optionally substituted group selected from C₁₋₆ aliphatic,        3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having        1-5 heteroatoms independently selected from nitrogen, oxygen, or        sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having        1-5 heteroatoms independently selected from nitrogen, oxygen, or        sulfur;    -   wherein each occurrence of R^(5b) is independently hydrogen or        an optionally substituted group selected from C₁₋₆ aliphatic,        3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having        1-5 heteroatoms independently selected from nitrogen, oxygen, or        sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having        1-5 heteroatoms independently selected from nitrogen, oxygen, or        sulfur; or two occurrences of R^(5b) taken together with the        nitrogen atom to which they are bound, form an optionally        substituted group selected from 3-6-membered heterocyclyl having        1-5 heteroatoms independently selected from nitrogen, oxygen, or        sulfur, or 5-10-membered heteroaryl having 1-5 heteroatoms        independently selected from nitrogen, oxygen, or sulfur;        provided that:        a) for compounds of formula IB compounds are other than:

and

-   -   when G¹ is CR⁸, R¹ is CONH₂, and W is NH, then HY is other than

andb) the compound is other than:

In another aspect, the compounds of this invention are represented byformula IA or IB:

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is —C(O)N(R³)₂, —C(O)OR³, —C(O)(NH)OH, —C(═NH)NHOH, —C(O)NR³N(R³)₂,—C(═N—NH₂)NH₂, —C(═N)N(R³)₂;

-   -   each occurrence of R³ is independently hydrogen or an optionally        substituted C₁₋₆ aliphatic;

Ring A is a group selected from 3-10-membered cycloaliphatic,4-10-membered heterocyclyl having 1-5 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-memberedheteroaryl having 1-5 heteroatoms independently selected from nitrogen,oxygen, or sulfur;

each occurrence of R² is independently —R^(12a), -T₂-R^(12d), or—V₂-T₂-R^(12d), and:

-   -   each occurrence of R^(12a) is independently halogen, —CN, —NO₂,        —R^(12c), —N(R^(12b))₂, —OR^(12b), —SR^(12c), —S(O)₂R^(12c),        —C(O)R^(12b), —C(O)OR^(12b), —C(O)N(R^(12b))₂, S(O)₂N(R^(12b))₂,        —OC(O)N(R^(12b))₂, —N(R^(12e))C(O)R^(12b),        —N(R^(12e))SO₂R^(12c), —N(R^(12e))C(O)OR^(12b),        —N(R^(12e))C(O)N(R^(12b))₂ or —N(R^(12e))SO₂N(R^(12b))₂, or two        occurrences of R^(12b), taken together with a nitrogen atom to        which they are bound, form an optionally substituted        4-7-membered heterocyclyl ring having 0-1 additional heteroatoms        selected from nitrogen, oxygen, or sulfur;    -   each occurrence of R^(12b) is independently hydrogen or an        optionally substituted group selected from C₁-C₆ aliphatic,        3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having        1-5 heteroatoms independently selected from nitrogen, oxygen, or        sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having        1-5 heteroatoms independently selected from nitrogen, oxygen, or        sulfur;    -   each occurrence of R^(12C) is independently an optionally        substituted group selected from C₁-C₆ aliphatic, 3-10-membered        cycloaliphatic, 4-10-membered heterocyclyl having 1-5        heteroatoms independently selected from nitrogen, oxygen, or        sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having        1-5 heteroatoms independently selected from nitrogen, oxygen, or        sulfur;    -   each occurrence of R^(12d) is independently hydrogen or an        optionally substituted from 3-10-membered cycloaliphatic,        4-10-membered heterocyclyl having 1-5 heteroatoms independently        selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl,        or 5-10-membered heteroaryl having 1-5 heteroatoms independently        selected from nitrogen, oxygen, or sulfur;    -   each occurrence of R^(12e) is independently hydrogen or an        optionally substituted C₁₋₆ aliphatic group;    -   each occurrence of V₂ is independently —N(R^(12e))—, —O—, —S—,        —S(O)—, —S(O)₂—, —C(O)—, —C(O)O—, —C(O)N(R^(12e))—,        —S(O)₂N(R^(12e))—, —OC(O)N(R^(12e))—, —N(R^(12e))C(O)—,        —N(R^(12e))SO₂—, —N(R^(12e))C(O)O—, —N(R^(12e))C(O)N(R^(12e))—,        —N(R^(12e))SO₂N(R^(12e))—, —OC(O)—, or —C(O)N(R^(12e))—O—; and

T₂ is an optionally substituted C₁-C₆ alkylene chain wherein thealkylene chain optionally is interrupted by —N(R¹³)—, —O—, —S—, —S(O)—,—S(O)₂—, —C(O)—, —C(O)O—, —C(O)N(R¹³)—, —S(O)₂N(R¹³)—, —OC(O)N(R¹³)—,—N(R¹³)C(O)—, —N(R¹³)SO₂—, —N(R¹³)C(O)O—, —N(R¹³)C(O)N(R¹³)—,—N(R¹³)S(O)₂N(R¹³)—, —OC(O)—, or —C(O)N(R¹³)—O— or wherein T₂ or aportion thereof optionally forms part of an optionally substituted 3-7membered cycloaliphatic or heterocyclyl ring, wherein R¹³ is hydrogen oran optionally substituted C₁₋₄aliphatic group;

n is 0 to 4;

W is selected from —C(R⁷)₂—, —C(═C(R⁷)₂)—, —C(R⁷)₂O—, —C(R⁷)₂NR^(7a)—,—O—, —N(R^(7b))—, —S—, —S(O)—, —S(O)₂—, —C(O)—, —C(O)NR^(7a)—, or—N(R^(7a))C(O)—, wherein:

-   -   each occurrence of R⁷ is independently hydrogen, or an        optionally substituted group selected from C₁₋₆ aliphatic,        6-10-membered aryl, 5-10-membered heteroaryl having 1-5        heteroatoms independently selected from nitrogen, oxygen, or        sulfur, —N(R^(7b))₂, —OR^(7a), —SR^(7a), halo, or —CN;    -   each occurrence of R^(7a) is independently hydrogen or        optionally substituted C₁₋₆ aliphatic or optionally substituted        C₃₋₆ cycloaliphatic;    -   each occurrence of R^(7b) is independently hydrogen, optionally        substituted C₁₋₆ aliphatic, optionally substituted C₃₋₆        cycloaliphatic, —C(O)R^(7a), —C(O)OR^(7a), S(O)R^(7a), or        —S(O)₂R^(7a); or    -   wherein any two occurrences of R⁷, R^(7a), or R^(7b) taken        together with the atom to which they are bound, form an        optionally substituted group selected from a 3-6-membered        cycloaliphatic ring, 6-10-membered aryl, 3-6-membered        heterocyclyl having 1-5 heteroatoms independently selected from        nitrogen, oxygen, or sulfur, or 5-10-membered heteroaryl having        1-5 heteroatoms independently selected from nitrogen, oxygen, or        sulfur;    -   or wherein any two occurrences of R^(7a) and R², or R^(7b) and        R² taken together with the nitrogen atom to which they are        bound, form an optionally substituted group selected from        3-6-membered heterocyclyl having 1-5 heteroatoms independently        selected from nitrogen, oxygen, or sulfur, or 5-10-membered        heteroaryl having 1-5 heteroatoms independently selected from        nitrogen, oxygen, or sulfur;    -   G₁ is N; and

HY is

wherein each occurrence of R¹⁴ is independently R^(14a) or -T₁-R^(14d)wherein:

-   -   each occurrence of R^(14a), as valency and stability permit, is        independently fluorine, ═O, ═S, —CN, —NO₂, —R^(14c),        —N(R^(14b))₂, —OR^(14b), —SR^(14c), —S(O)₂R^(14c), —C(O)R^(14b),        —C(O)OR^(14b), —C(O)N(R^(14b))₂, —S(O)₂N(R^(14b))₂,        —OC(O)N(R^(14b))₂, —N(R^(14e))C(O)R^(14b),        —N(R^(14e))SO₂R^(14c), —N(R^(14e))C(O)OR^(14b),        —N(R^(14e))C(O)N(R^(14b))₂, or N(R^(14e))SO₂N(R^(14b))₂, or two        occurrences of R^(14b), taken together with a nitrogen atom to        which they are bound, form an optionally substituted        4-7-membered heterocyclyl ring having 0-1 additional heteroatoms        selected from nitrogen, oxygen, or sulfur;    -   each occurrence of R^(14b) is independently hydrogen or an        optionally substituted group selected from C₁-C₆ aliphatic,        3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having        1-5 heteroatoms independently selected from nitrogen, oxygen, or        sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having        1-5 heteroatoms independently selected from nitrogen, oxygen, or        sulfur;    -   each occurrence of R^(14c) is independently an optionally        substituted group selected from C₁-C₆ aliphatic, 3-10-membered        cycloaliphatic, 4-10-membered heterocyclyl having 1-5        heteroatoms independently selected from nitrogen, oxygen, or        sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having        1-5 heteroatoms independently selected from nitrogen, oxygen, or        sulfur;    -   each occurrence of R^(14d) is independently hydrogen or an        optionally substituted from 3-10-membered cycloaliphatic,        4-10-membered heterocyclyl having 1-5 heteroatoms independently        selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl,        or 5-10-membered heteroaryl having 1-5 heteroatoms independently        selected from nitrogen, oxygen, or sulfur;    -   each occurrence of R^(14e) is independently hydrogen or an        optionally substituted C₁₋₆ aliphatic group; and    -   T₁ is an optionally substituted C₁-C₆ alkylene chain wherein the        alkylene chain optionally is interrupted        by —N(R^(14a))—, —O—, —S—, —S(O)—, —S(O)₂—, —C(O)—, —C(O)O—,        —C(O)N(R^(14a))—, —S(O)₂N(R^(14a))—, —OC(O)N(R^(14a))—,        —N(R^(14a))C(O)—, —N(R^(14a))SO₂—, —N(R^(14a))C(O)O—,        —NR^(14a)C(O)N(R^(14a))—, —N(R^(14a))S(O)₂N(R^(14a))—, —OC(O)—,        or —C(O)N(R^(14a))—O— or wherein T₁ or a portion thereof        optionally forms part of an optionally substituted 3-7 membered        cycloaliphatic or heterocyclyl ring;

n is 0-6;

m is 1 or 2;

p is 0, 1, or 2;

provided that the compound is other than:

In some embodiments for compounds described directly above, HY is

wherein both occurrences of m are 1.

In other embodiments for compounds described directly above, HY is

wherein both occurrences of m are 1, and R¹ is COOH.

In yet another aspect, the compounds of this invention are representedby formula IA or IB:

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is CY, wherein:

-   -   CY is an optionally substituted group selected from:

wherein:

-   -   each occurrence of R³ is independently hydrogen or an optionally        substituted C₁₋₆ aliphatic, wherein:    -   X₈, X₉, X₁₀, and X₁₁ are each independently N, or CR⁴, provided        no more than two occurrences of X₈, X₉, X₁₀, and X₁₁ are N;    -   each occurrence of R⁴ is independently hydrogen, —CN, halogen,        Z₃—R⁶, or an optionally substituted group selected from C₁₋₆        aliphatic, or 3-10-membered cycloaliphatic, wherein:        -   Z₃ is selected from an optionally substituted C₁₋₃ alkylene            chain, —O—, —N(R^(4a))—, —S—, —S(O)—, —S(O)₂—, —C(O)—,            —CO₂—, —C(O)NR^(4a)—, —N(R^(4a))C(O)—, —N(R^(4a))CO₂—,            —S(O)₂NR^(4a)—, —N(R^(4a))S(O)₂—, —OC(O)N(R^(4a))—,            —N(R^(4a))C(O)NR^(4a)—, —N(R^(4a))S(O)₂N(R^(4a))—, or            —OC(O)—;        -   R^(4a) is hydrogen or an optionally substituted C₁₋₄            aliphatic, and        -   R⁶ is hydrogen or an optionally substituted group selected            from C₁₋₆ aliphatic,    -   3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having        1-5 heteroatoms independently selected from nitrogen, oxygen, or        sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having        1-5 heteroatoms independently selected from nitrogen, oxygen, or        sulfur;    -   Y₁₀ is —OR^(4′) or —N(R^(4′))₂;    -   Y₁₁ is O or N—R^(4′);    -   each occurrence of R^(4′) is independently hydrogen or an        optionally substituted C₁₋₆ aliphatic;

Ring A is a group selected from 3-10-membered cycloaliphatic,4-10-membered heterocyclyl having 1-5 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-memberedheteroaryl having 1-5 heteroatoms independently selected from nitrogen,oxygen, or sulfur;

each occurrence of R² is independently R^(12a), -T₂-R^(12d), orV₂-T₂-R^(12d), and:

-   -   each occurrence of R^(12a) is independently halogen, —CN, —NO₂,        —R^(12c), —N(R^(12b))₂OR^(12b), —SR^(12c), —S(O)₂R^(12c),        —C(O)R^(12b), —C(O)OR^(12b), —C(O)N(R^(12b))₂,        —S(O)₂N(R^(12b))₂, —OC(O)N(R^(12b))₂, —N(R^(12e))C(O)R^(12b),        —N(R^(12e))SO₂R^(12c), —N(R^(12e))C(O)OR^(12b),        —N(R^(12e))C(O)N(R^(12b))₂, or N(R^(12e))SO₂N(R^(12b))₂, or two        occurrences of R^(12b), taken together with a nitrogen atom to        which they are bound, form an optionally substituted        4-7-membered heterocyclyl ring having 0-1 additional heteroatoms        selected from nitrogen, oxygen, or sulfur;    -   each occurrence of R^(12b) is independently hydrogen or an        optionally substituted group selected from C₁-C₆ aliphatic,        3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having        1-5 heteroatoms independently selected from nitrogen, oxygen, or        sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having        1-5 heteroatoms independently selected from nitrogen, oxygen, or        sulfur;    -   each occurrence of R^(12C) is independently an optionally        substituted group selected from C₁-C₆ aliphatic, 3-10-membered        cycloaliphatic, 4-10-membered heterocyclyl having 1-5        heteroatoms independently selected from nitrogen, oxygen, or        sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having        1-5 heteroatoms independently selected from nitrogen, oxygen, or        sulfur;    -   each occurrence of R^(12d) is independently hydrogen or an        optionally substituted from 3-10-membered cycloaliphatic,        4-10-membered heterocyclyl having 1-5 heteroatoms independently        selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl,        or 5-10-membered heteroaryl having 1-5 heteroatoms independently        selected from nitrogen, oxygen, or sulfur;    -   each occurrence of R^(12e) is independently hydrogen or an        optionally substituted C₁₋₆ aliphatic group;    -   each occurrence of V₂ is independently —N(R^(12e))—, —O—, —S—,        —S(O)—, —S(O)₂—, —C(O)—, —C(O)O—, —C(O)N(R^(12e))—,        —S(O)₂N(R^(12e))—, —OC(O)N(R^(12e))—, —N(R^(12e))C(O)—,        —N(R^(12e))SO₂—, —N(R^(12e))C(O)O—, —N(R^(12e))C(O)N(R^(12e))—,        —N(R^(12e))SO₂N(R^(12e))—, —OC(O)—, or —C(O)N(R^(12e))—O—; and

T₂ is an optionally substituted C₁-C₆ alkylene chain wherein thealkylene chain optionally is interrupted by —N(R¹³)—, —O—, —S—, —S(O)—,—S(O)₂—, —C(O)—, —C(O)O—, —C(O)N(R¹³)—, —S(O)₂N(R¹³)—, —OC(O)N(R¹³)—,—N(R¹³)C(O)—, —N(R¹³)SO₂—, —N(R¹³)C(O)O—, —N(R¹³)C(O)N(R¹³)—,—N(R¹³)S(O)₂N(R¹³)—, —OC(O)—, or —C(O)N(R¹³)—O— or wherein T₂ or aportion thereof optionally forms part of an optionally substituted 3-7membered cycloaliphatic or heterocyclyl ring, wherein R¹³ is hydrogen oran optionally substituted C₁₋₄aliphatic group;

n is 0 to 4;

W is selected from —C(R⁷)₂—, —C(═C(R⁷)₂)—, —C(R⁷)₂O—, —C(R⁷)₂NR^(7a)—,—O—, —N(R^(7b))—, —S—, —S(O)—, —S(O)₂—, —C(O)—, —C(O)NR^(7a)—, or—N(R^(7a))C(O)—, wherein:

-   -   each occurrence of R⁷ is independently hydrogen, or an        optionally substituted group selected from C₁₋₆ aliphatic,        6-10-membered aryl, 5-10-membered heteroaryl having 1-5        heteroatoms independently selected from nitrogen, oxygen, or        sulfur, —N(R^(7b))₂, —OR^(7a), —SR^(7a), halo, or —CN;    -   each occurrence of R^(7a) is independently hydrogen or        optionally substituted C₁₋₆ aliphatic or optionally substituted        C₃₋₆ cycloaliphatic;    -   each occurrence of R^(7b) is independently hydrogen, optionally        substituted C₁₋₆ aliphatic, optionally substituted C₃₋₆        cycloaliphatic, —C(O)R^(7a), —C(O)OR^(7a), S(O)R^(7a), or        —S(O)₂R^(7a); or    -   wherein any two occurrences of R⁷, R^(7a), or R^(7b) taken        together with the atom to which they are bound, form an        optionally substituted group selected from a 3-6-membered        cycloaliphatic ring, 6-10-membered aryl, 3-6-membered        heterocyclyl having 1-5 heteroatoms independently selected from        nitrogen, oxygen, or sulfur, or 5-10-membered heteroaryl having        1-5 heteroatoms independently selected from nitrogen, oxygen, or        sulfur;    -   or wherein any two occurrences of R^(7a) and R², or R^(7b) and        R² taken together with the nitrogen atom to which they are        bound, form an optionally substituted group selected from        3-6-membered heterocyclyl having 1-5 heteroatoms independently        selected from nitrogen, oxygen, or sulfur, or 5-10-membered        heteroaryl having 1-5 heteroatoms independently selected from        nitrogen, oxygen, or sulfur;

G₁ is N or —CR⁸, wherein R⁸ is H, —CN, halogen, —Z₂—R⁹, C₁₋₆ aliphatic,or 3-10-membered cycloaliphatic, wherein:

-   -   Z₂ is selected from an optionally substituted C₁₋₃ alkylene        chain, —O—, —N(R^(8a))—, —S—, —S(O)—, S(O)₂—, —C(O)—, —CO₂—,        —C(O)NR^(8a)—, —N(R^(8a))C(O)—, —N(R^(8a))CO₂—, —S(O)₂NR^(8a)—,        —N(R^(8a))S(O)₂—, —OC(O)N(R^(8a))—, —N(R^(8a))C(O)NR^(8a)—,        —N(R^(8a))S(O)₂N(R^(8a))—, or —OC(O)—;        -   R^(8a) is hydrogen or an optionally substituted C₁₋₄            aliphatic, and    -   R⁹ is hydrogen or an optionally substituted group selected from        C₁₋₆ aliphatic, 3-10-membered cycloaliphatic, 4-10-membered        heterocyclyl having 1-5 heteroatoms independently selected from        nitrogen, oxygen, or sulfur, 6-10-membered aryl, or        5-10-membered heteroaryl having 1-5 heteroatoms independently        selected from nitrogen, oxygen, or sulfur; and

HY is

wherein each occurrence of R¹⁴ is independently —R^(14a) or -T₁-R^(14d),wherein:

-   -   each occurrence of R^(14a), as valency and stability permit, is        independently fluorine, ═O, ═S, —CN, —NO₂, —R^(14e),        —N(R^(14b))₂, —OR^(14b), —SR^(14e), —S(O)₂R^(14e), —C(O)R^(14b),        —C(O)OR^(14b), —C(O)N(R^(14b))₂, —S(O)₂N(R^(14b))₂,        —OC(O)N(R^(14b))₂, —N(R^(14e))C(O)R^(14b),        —N(R^(14e))SO₂R^(14e), —N(R^(14e))C(O)OR^(14b),        —N(R^(14e))C(O)N(R^(14b))₂, or —N(R^(14e))SO₂N(R^(14b))₂, or two        occurrences of R^(14b), taken together with a nitrogen atom to        which they are bound, form an optionally substituted        4-7-membered heterocyclyl ring having 0-1 additional heteroatoms        selected from nitrogen, oxygen, or sulfur;    -   each occurrence of R^(14b) is independently hydrogen or an        optionally substituted group selected from C₁-C₆ aliphatic,        3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having        1-5 heteroatoms independently selected from nitrogen, oxygen, or        sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having        1-5 heteroatoms independently selected from nitrogen, oxygen, or        sulfur;    -   each occurrence of R^(14c) is independently an optionally        substituted group selected from C₁-C₆ aliphatic, 3-10-membered        cycloaliphatic, 4-10-membered heterocyclyl having 1-5        heteroatoms independently selected from nitrogen, oxygen, or        sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having        1-5 heteroatoms independently selected from nitrogen, oxygen, or        sulfur;    -   each occurrence of R^(14d) is independently hydrogen or an        optionally substituted from 3-10-membered cycloaliphatic,        4-10-membered heterocyclyl having 1-5 heteroatoms independently        selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl,        or 5-10-membered heteroaryl having 1-5 heteroatoms independently        selected from nitrogen, oxygen, or sulfur;    -   each occurrence of R^(14e) is independently hydrogen or an        optionally substituted C₁₋₆ aliphatic group; and    -   T₁ is an optionally substituted C₁-C₆ alkylene chain wherein the        alkylene chain optionally is interrupted    -   by —N(R^(14a))—, —O—, —S—, —S(O)—, —S(O)₂—, —C(O)—, —C(O)O—,        —C(O)N(R^(14a))—, —S(O)₂N(R^(14a))—, —OC(O)N(R^(14a))—,        —N(R^(14a))C(O)—, —N(R^(14a))SO₂—, —N(R^(14a))C(O)O—,        —NR^(14a)C(O)N(R^(14a))—, —N(R^(14a))S(O)₂N(R^(14a))—, —OC(O)—,        or —C(O)N(R^(14a))—O— or wherein T₁ or a portion thereof        optionally forms part of an optionally substituted 3-7 membered        cycloaliphatic or heterocyclyl ring;

n is 0-6;

m is 1 or 2; and

p is 0, 1, or 2.

In still another embodiment of the invention, compounds of thisinvention are represented by formula IA-i-a or IB-i-a:

or a pharmaceutically acceptable salt thereof, wherein:

Z is S or Se;

R³ is hydrogen or an optionally substituted C₁₋₆ aliphatic;

Ring A is a group selected from 3-10-membered cycloaliphatic,4-10-membered heterocyclyl having 1-5 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-memberedheteroaryl having 1-5 heteroatoms independently selected from nitrogen,oxygen, or sulfur;

each occurrence of R² is independently R^(12a), -T₂-R^(12d), orV₂-T₂-R^(12d), or:

-   -   two adjacent R² groups are taken together with their intervening        atoms to form an optionally substituted 4-7 membered saturated,        partially unsaturated, or aryl ring having 0-4 heteroatoms        selected from nitrogen, oxygen, or sulfur;    -   each occurrence of R¹² is independently halogen, —CN, —NO₂,        —R^(12c), —N(R^(12b))₂, —OR^(12b), —SR^(12c), —S(O)₂R^(12c),        —C(O)R^(12b), —C(O)OR^(12b), —C(O)N(R^(12b))₂,        —S(O)₂N(R^(12b))₂, —OC(O)N(R^(12b))₂, —N(R^(12e))C(O)R^(12b),        —N(R^(12e))SO₂R^(12c), —N(R^(12e))C(O)OR^(12b),        —N(R^(12e))C(O)N(R¹²)₂, or —N(R^(12e))SO₂N(R^(12b))₂;    -   each occurrence of R^(12b) is independently hydrogen or an        optionally substituted group selected from C₁₋₆ aliphatic,        3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having        1-5 heteroatoms independently selected from nitrogen, oxygen, or        sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having        1-5 heteroatoms independently selected from nitrogen, oxygen, or        sulfur, or two occurrences of R^(12b), taken together with a        nitrogen atom to which they are bound, form an optionally        substituted 4-7-membered heterocyclyl ring having 0-1 additional        heteroatoms selected from nitrogen, oxygen, or sulfur;    -   each occurrence of R^(12C) is independently an optionally        substituted group selected from C₁₋₆ aliphatic, 3-10-membered        cycloaliphatic, 4-10-membered heterocyclyl having 1-5        heteroatoms independently selected from nitrogen, oxygen, or        sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having        1-5 heteroatoms independently selected from nitrogen, oxygen, or        sulfur;    -   each occurrence of R^(12d) is independently hydrogen,        —N(R^(7b))₂, or an optionally substituted group selected from        3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having        1-5 heteroatoms independently selected from nitrogen, oxygen, or        sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having        1-5 heteroatoms independently selected from nitrogen, oxygen, or        sulfur;    -   each occurrence of R^(12e) is independently hydrogen or an        optionally substituted C₁₋₆ aliphatic group;    -   each occurrence of V₂ is independently —N(R^(12e))—, —O—, —S—,        —S(O)—, —S(O)₂—, —C(O)—, —C(O)O—, —C(O)N(R^(12e))—,        —S(O)₂N(R^(12e))—, —OC(O)N(R^(12e))—, —N(R^(12e))C(O)—,        —N(R^(12e))SO₂—, —N(R^(12e))C(O)O—, —N(R^(12e))C(O)N(R^(12e))—,        —N(R^(12e))SO₂N(R^(12e))—, —OC(O)—, or —C(O)N(R^(12e))—O—; and

T₂ is an optionally substituted C₁₋₆ alkylene chain wherein the alkylenechain optionally is interrupted by —N(R¹³)—, —O—, —S—, —S(O)—, —S(O)₂—,—C(O)—, —C(O)O—, —C(O)N(R¹³)—, —S(O)₂N(R¹³)—, —OC(O)N(R¹³)—,—N(R¹³)C(O)—, —N(R¹³)SO₂—, —N(R¹³)C(O)O—, —N(R¹³)C(O)N(R¹³)—,—N(R¹³)S(O)₂N(R¹³)—, —OC(O)—, or —C(O)N(R¹³)—O— or wherein T₂ or aportion thereof optionally forms part of an optionally substituted 3-7membered cycloaliphatic or heterocyclyl ring, wherein R¹³ is hydrogen oran optionally substituted C₁₋₄aliphatic group;

W is selected from a covalent bond, —C(R⁷)₂—, —C(═C(R⁷)₂)—, —C(R⁷)₂O—,—C(R⁷)₂NR^(7a)—, —O—, —N(R^(7b))—, —S—, —S(O)—, —S(O)₂—, —C(O)—,—C(O)NR^(7a)—, or —N(R^(7a))C(O)—, wherein:

-   -   each occurrence of R⁷ is independently hydrogen, or an        optionally substituted group selected from C₁₋₆ aliphatic,        6-10-membered aryl, 5-10-membered heteroaryl having 1-5        heteroatoms independently selected from nitrogen, oxygen, or        sulfur, —N(R^(7b))₂, —OR^(7c), —SR^(7a), or F;    -   each occurrence of R^(7a) is independently hydrogen or        optionally substituted C₁₋₆ aliphatic;    -   each occurrence of R^(7b) is independently hydrogen, optionally        substituted C₁₋₆ aliphatic, —C(O)R^(7a), —C(O)OR^(7a),        S(O)R^(7a), or —S(O)₂R^(7a); or    -   each occurrence of R^(7c) is independently an optionally        substituted C₁₋₆aliphatic or an optionally substituted 3-7        membered cycloaliphatic; or    -   wherein any two occurrences of R⁷, R^(7a), R^(7b), or R^(7c),        taken together with atom to which they are bound, form an        optionally substituted group selected from a 3-6-membered        cycloaliphatic ring, 6-10-membered aryl, 3-6-membered        heterocyclyl having 1-5 heteroatoms independently selected from        nitrogen, oxygen, or sulfur, or 5-10-membered heteroaryl having        1-5 heteroatoms independently selected from nitrogen, oxygen, or        sulfur;    -   or wherein any two occurrences of R^(7a) and R², or R^(7b) and        R² taken together with the nitrogen atom to which they are        bound, form an optionally substituted group selected from        3-6-membered heterocyclyl having 1-5 heteroatoms independently        selected from nitrogen, oxygen, or sulfur, or 5-10-membered        heteroaryl having 1-5 heteroatoms independently selected from        nitrogen, oxygen, or sulfur;

G₁ is N or —CR⁸, wherein R⁸ is H, —CN, halogen, —Z₂—R⁹, C₁₋₆ aliphatic,or 3-10-membered cycloaliphatic, wherein:

-   -   Z₂ is selected from an optionally substituted C₁₋₃ alkylene        chain, —O—, —N(R^(8a))—, —S—, —S(O)—, S(O)₂—, —C(O)—, —CO₂—,        —C(O)NR^(8a)—, —N(R^(8a))C(O)—, —N(R^(8a))CO₂—, —S(O)₂NR^(8a)—,        —N(R^(8a))S(O)₂—, —OC(O)N(R^(8a))—, —N(R^(8a))C(O)NR^(8a)—,        —N(R^(8a))S(O)₂N(R^(8a))—, or —OC(O)—;        -   R^(8a) is hydrogen or an optionally substituted C₁₋₄            aliphatic, and    -   R⁹ is hydrogen or an optionally substituted group selected from        C₁₋₆ aliphatic, 3-10-membered cycloaliphatic, 4-10-membered        heterocyclyl having 1-5 heteroatoms independently selected from        nitrogen, oxygen, or sulfur, 6-10-membered aryl, or        5-10-membered heteroaryl having 1-5 heteroatoms independently        selected from nitrogen, oxygen, or sulfur; and

HY is

represents a single bond or a double bond;

wherein each occurrence of R¹⁴ is independently R^(14a) or -T₁-R^(14d),wherein:

-   -   each occurrence of R^(14a), as valency and stability permit, is        independently fluorine, ═O, ═S, —CN, —NO₂, —R^(14c),        —N(R^(14b))₂, —OR^(14b), SR^(14c), —S(O)₂R^(14c), —C(O)R^(14b),        —C(O)OR^(14b), —C(O)N(R^(14b))₂, —S(O)₂N(R^(14b))₂,        —OC(O)N(R^(14b))₂, —N(R^(14e))C(O)R^(14b),        —N(R^(14e))SO₂R^(14c), —N(R^(14e))C(O)OR^(14b),        —N(R^(14e))C(O)N(R^(14b))₂, or —N(R^(14e))SO₂N(R^(14b))₂, or two        occurrences of R^(14b), taken together with a nitrogen atom to        which they are bound, form an optionally substituted        4-7-membered heterocyclyl ring having 0-1 additional heteroatoms        selected from nitrogen, oxygen, or sulfur;    -   each occurrence of R^(14b) is independently hydrogen or an        optionally substituted group selected from C₁₋₆ aliphatic,        3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having        1-5 heteroatoms independently selected from nitrogen, oxygen, or        sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having        1-5 heteroatoms independently selected from nitrogen, oxygen, or        sulfur;    -   each occurrence of R^(14c) is independently an optionally        substituted group selected from C₁₋₆ aliphatic, 3-10-membered        cycloaliphatic, 4-10-membered heterocyclyl having 1-5        heteroatoms independently selected from nitrogen, oxygen, or        sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having        1-5 heteroatoms independently selected from nitrogen, oxygen, or        sulfur;    -   each occurrence of R^(14d) is independently hydrogen or an        optionally substituted from 3-10-membered cycloaliphatic,        4-10-membered heterocyclyl having 1-5 heteroatoms independently        selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl,        or 5-10-membered heteroaryl having 1-5 heteroatoms independently        selected from nitrogen, oxygen, or sulfur;    -   each occurrence of R^(14e) is independently hydrogen or an        optionally substituted C₁₋₆ aliphatic group; and    -   T₁ is an optionally substituted C₁₋₆ alkylene chain wherein the        alkylene chain optionally is interrupted by —N(R^(14a))—, —O—,        —S—, —S(O)—, —S(O)₂—, —C(O)—, —C(O)O—, —C(O)N(R^(14a))—,        —S(O)₂N(R^(14a))—, —OC(O)N(R^(14a))—, —N(R^(14a))C(O)—,        —N(R^(14a))SO₂—, —N(R^(14a))C(O)O—, —NR^(14a)C(O)N(R^(14a))—,        —N(R^(14a))S(O)₂N(R^(14a))—, —OC(O)—, or —C(O)N(R^(14a))—O— or        wherein T₁ or a portion thereof optionally forms part of an        optionally substituted 3-7 membered cycloaliphatic or        heterocyclyl ring;

n is 0-6;

q is 0-4;

m is 1 or 2; and

p is 0, 1, or 2;

provided that:a) when G₁ is C—CN, HY is unsubstituted morpholine, R¹ is —C(O)OH,—C(O)OMe, or —C(O)OEt, and W is a covalent bond, then Ring A is otherthan unsubstituted phenyl, 2-chlorophenyl, 4-chlorophenyl,2-fluorophenyl, 4-fluorophenyl, 2,4-dichlorophenyl, 3,4-dichlorophenyl,4-methylphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3,4-dimethoxyphenyl,3-(trifluoromethyl)phenyl, 4-(trifluoromethyl)phenyl, or3-(acetylamino)phenyl;b) when G₁ is N, HY is unsubstituted morpholine, R¹ is —C(O)OH,—C(O)OMe, or —C(O)OEt, and W is a covalent bond, then Ring A is otherthan unsubstituted phenyl or 2-chlorophenyl; andc) the compound is other than:

In yet another embodiment of the invention, compounds of this inventionare represented by formula IA-i or IB-i:

or a pharmaceutically acceptable salt thereof, wherein:

R³ is hydrogen or an optionally substituted C₁₋₆ aliphatic;

Ring A is a group selected from 3-10-membered cycloaliphatic,4-10-membered heterocyclyl having 1-5 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-memberedheteroaryl having 1-5 heteroatoms independently selected from nitrogen,oxygen, or sulfur;

each occurrence of R² is independently R^(12a), -T₂-R^(12d), or—V₂-T₂-R^(12d), or:

-   -   two adjacent R² groups are taken together with their intervening        atoms to form an optionally substituted 4-7 membered saturated,        partially unsaturated, or aryl ring having 0-4 heteroatoms        selected from nitrogen, oxygen, or sulfur;    -   each occurrence of R^(12a) is independently halogen, —CN, —NO₂,        —R^(12c), —N(R^(12b))₂, —OR^(12b), —SR^(12c), —S(O)₂R^(12c),        —C(O)R^(12b), —C(O)OR^(12b), —C(O)N(R^(12b))₂,        —S(O)₂N(R^(12b))₂, —OC(O)N(R^(12b))₂, —N(R^(12e))C(O)R^(12b),        —N(R^(12e))SO₂R^(12c), N(R^(12e))C(O)OR^(12b),        —N(R^(12e))C(O)N(R^(12b))₂, or —N(R^(12e))SO₂N(R^(12b))₂;    -   each occurrence of R^(12b) is independently hydrogen or an        optionally substituted group selected from C₁₋₆ aliphatic,        3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having        1-5 heteroatoms independently selected from nitrogen, oxygen, or        sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having        1-5 heteroatoms independently selected from nitrogen, oxygen, or        sulfur, or two occurrences of R^(12b), taken together with a        nitrogen atom to which they are bound, form an optionally        substituted 4-7-membered heterocyclyl ring having 0-1 additional        heteroatoms selected from nitrogen, oxygen, or sulfur;    -   each occurrence of R^(12c) is independently an optionally        substituted group selected from C₁₋₆ aliphatic, 3-10-membered        cycloaliphatic, 4-10-membered heterocyclyl having 1-5        heteroatoms independently selected from nitrogen, oxygen, or        sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having        1-5 heteroatoms independently selected from nitrogen, oxygen, or        sulfur;    -   each occurrence of R^(12d) is independently hydrogen,        —N(R^(7b))₂, or an optionally substituted group selected from        3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having        1-5 heteroatoms independently selected from nitrogen, oxygen, or        sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having        1-5 heteroatoms independently selected from nitrogen, oxygen, or        sulfur;    -   each occurrence of R^(12e) is independently hydrogen or an        optionally substituted C₁₋₆ aliphatic group;    -   each occurrence of V₂ is independently —N(R^(12e))—, —O—, —S—,        —S(O)—, —S(O)₂—, —C(O)—, —C(O)O—, —C(O)N(R^(12e))—,        —S(O)₂N(R^(12e))—, —OC(O)N(R^(12e))—, —N(R^(12e))C(O)—,        —N(R^(12e))SO₂—, —N(R^(12e))C(O)O—, —N(R^(12e))C(O)N(R^(12e))—,        —N(R^(12e))SO₂N(R^(12e))—, —OC(O)—, or —C(O)N(R^(12e))—O—; and

T₂ is an optionally substituted C₁₋₆ alkylene chain wherein the alkylenechain optionally is interrupted by —N(R¹³)—, —O—, —S—, —S(O)—, —S(O)₂—,—C(O)—, —C(O)O—, —C(O)N(R¹³)—, —S(O)₂N(R¹³)—, —OC(O)N(R¹³)—,—N(R¹³)C(O)—, —N(R¹³)SO₂—, —N(R¹³)C(O)O—, —N(R¹³)C(O)N(R¹³)—,—N(R¹³)S(O)₂N(R¹³)—, —OC(O)—, or —C(O)N(R¹³)—O— or wherein T₂ or aportion thereof optionally forms part of an optionally substituted 3-7membered cycloaliphatic or heterocyclyl ring, wherein R¹³ is hydrogen oran optionally substituted C₁₋₄aliphatic group;

W is selected from a covalent bond, —C(R⁷)₂—, —C(═C(R⁷)₂)—, —C(R⁷)₂O—,—C(R⁷)₂NR^(7a)—, —O—, —N(R^(7b))—, —S—, —S(O)—, —S(O)₂—, —C(O)—,—C(O)NR^(7a)—, or —N(R^(7a))C(O)—, wherein:

-   -   each occurrence of R⁷ is independently hydrogen, or an        optionally substituted group selected from C₁₋₆ aliphatic,        6-10-membered aryl, 5-10-membered heteroaryl having 1-5        heteroatoms independently selected from nitrogen, oxygen, or        sulfur, —N(R^(7b))₂, —OR^(7e), —SR^(7a), or F;    -   each occurrence of R^(7a) is independently hydrogen or        optionally substituted C₁₋₆ aliphatic or optionally substituted        C₃₋₆ cycloaliphatic;    -   each occurrence of R^(7b) is independently hydrogen, optionally        substituted C₁₋₆ aliphatic, optionally substituted C₃₋₆        cycloaliphatic, —C(O)R^(7a), —C(O)OR^(7a), S(O)R^(7a), or        —S(O)₂R^(7a); or    -   each occurrence of R^(7c) is independently an optionally        substituted C₁₋₆aliphatic or an optionally substituted 3-7        membered cycloaliphatic; or    -   wherein any two occurrences of R⁷, R^(7a), R^(7b), or R^(7c),        taken together with atom to which they are bound, form an        optionally substituted group selected from a 3-6-membered        cycloaliphatic ring, 6-10-membered aryl, 3-6-membered        heterocyclyl having 1-5 heteroatoms independently selected from        nitrogen, oxygen, or sulfur, or 5-10-membered heteroaryl having        1-5 heteroatoms independently selected from nitrogen, oxygen, or        sulfur;    -   or wherein any two occurrences of R^(7a) and R², or R^(7b) and        R² taken together with the nitrogen atom to which they are        bound, form an optionally substituted group selected from        3-6-membered heterocyclyl having 1-5 heteroatoms independently        selected from nitrogen, oxygen, or sulfur, or 5-10-membered        heteroaryl having 1-5 heteroatoms independently selected from        nitrogen, oxygen, or sulfur;

G₁ is N or —CR⁸, wherein R⁸ is H, —CN, halogen, —Z₂—R⁹, C₁₋₆ aliphatic,or 3-10-membered cycloaliphatic, wherein:

-   -   Z₂ is selected from an optionally substituted C₁₋₃ alkylene        chain, —O—, —N(R^(8a))—, —S—, —S(O)—, S(O)₂—, —C(O)—, —CO₂—,        —C(O)NR^(8a)—, —N(R^(8a))C(O)—, —N(R^(8a))CO₂—, —S(O)₂NR^(8a)—,        —N(R^(8a))S(O)₂—, —OC(O)N(R^(8a))—, —N(R^(8a))C(O)NR^(8a)—,        —N(R^(8a))S(O)₂N(R^(8a))—, or —OC(O)—;        -   R^(8a) is hydrogen or an optionally substituted C₁₋₄            aliphatic, and    -   R⁹ is hydrogen or an optionally substituted group selected from        C₁₋₆ aliphatic, 3-10-membered cycloaliphatic, 4-10-membered        heterocyclyl having 1-5 heteroatoms independently selected from        nitrogen, oxygen, or sulfur, 6-10-membered aryl, or        5-10-membered heteroaryl having 1-5 heteroatoms independently        selected from nitrogen, oxygen, or sulfur; and

HY is

represents a single bond or a double bond;

wherein each occurrence of R¹⁴ is independently —R^(14a) or -T₁-R^(14d)wherein:

-   -   each occurrence of R^(14a), as valency and stability permit, is        independently fluorine, ═O, ═S, —CN, —NO₂, —R^(14c),        —N(R^(14b))₂, OR^(14b), SR^(14c), —S(O)₂R^(14c), —C(O)R^(14b),        —C(O)OR^(14b), —C(O)N(R^(14b))₂, —S(O)₂N(R^(14b))₂,        —OC(O)N(R^(14b))₂, —N(R^(14e))C(O)R^(14b),        —N(R^(14e))SO₂R^(14c), —N(R^(14e))C(O)OR^(14b),        —N(R^(14e))C(O)N(R^(14b))₂, or —N(R^(14e))SO₂N(R^(14b))₂, or two        occurrences of R^(14b), taken together with a nitrogen atom to        which they are bound, form an optionally substituted        4-7-membered heterocyclyl ring having 0-1 additional heteroatoms        selected from nitrogen, oxygen, or sulfur;    -   each occurrence of R^(14b) is independently hydrogen or an        optionally substituted group selected from C₁₋₆ aliphatic,        3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having        1-5 heteroatoms independently selected from nitrogen, oxygen, or        sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having        1-5 heteroatoms independently selected from nitrogen, oxygen, or        sulfur;    -   each occurrence of R^(14c) is independently an optionally        substituted group selected from C₁₋₆ aliphatic, 3-10-membered        cycloaliphatic, 4-10-membered heterocyclyl having 1-5        heteroatoms independently selected from nitrogen, oxygen, or        sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having        1-5 heteroatoms independently selected from nitrogen, oxygen, or        sulfur;    -   each occurrence of R^(14d) is independently hydrogen or an        optionally substituted from 3-10-membered cycloaliphatic,        4-10-membered heterocyclyl having 1-5 heteroatoms independently        selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl,        or 5-10-membered heteroaryl having 1-5 heteroatoms independently        selected from nitrogen, oxygen, or sulfur;    -   each occurrence of R^(14e) is independently hydrogen or an        optionally substituted C₁₋₆ aliphatic group; and    -   T₁ is an optionally substituted C₁₋₆ alkylene chain wherein the        alkylene chain optionally is interrupted by —N(R^(14a))—, —O—,        —S—, —S(O)—, —S(O)₂—, —C(O)—, —C(O)O—, —C(O)N(R^(14a))—,        —S(O)₂N(R^(14a))—, —OC(O)N(R^(14a))—, —N(R^(14a))C(O)—,        —N(R^(14a))SO₂—, —N(R^(14a))C(O)O—, —NR^(14a)C(O)N(R^(14a))—,        —N(R^(14a))S(O)₂N(R^(14a))—, —OC(O)—, or —C(O)N(R^(14a))—O— or        wherein T₁ or a portion thereof optionally forms part of an        optionally substituted 3-7 membered cycloaliphatic or        heterocyclyl ring;

n is 0-6;

q is 0-4;

m is 1 or 2; and

p is 0, 1, or 2;

provided that:a) when G₁ is C—CN, HY is unsubstituted morpholine, R¹ is —C(O)OH,—C(O)OMe, or —C(O)OEt, and W is a covalent bond, then Ring A is otherthan unsubstituted phenyl, 2-chlorophenyl, 4-chlorophenyl,2-fluorophenyl, 4-fluorophenyl, 2,4-dichlorophenyl, 3,4-dichlorophenyl,4-methylphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3,4-dimethoxyphenyl,3-(trifluoromethyl)phenyl, 4-(trifluoromethyl)phenyl, or3-(acetylamino)phenyl;b) when G₁ is N, HY is unsubstituted morpholine, R¹ is —C(O)OH,—C(O)OMe, or —C(O)OEt, and W is a covalent bond, then Ring A is otherthan unsubstituted phenyl or 2-chlorophenyl; andc) the compound is other than:

In some embodiments for compounds described directly above, G₁ is N.

In some embodiments for compounds described directly above, G₁ is C(R⁸),wherein R⁸ is CN or C₂₋₄ alkynyl.

In some embodiments for compounds described directly above, HY is

wherein both occurrences of m are 1.

In some embodiments for compounds described directly above, R³ is H.

DETAILED DESCRIPTION OF THE INVENTION 2. Compounds and Definitions

Compounds of this invention include those described generally above, andare further illustrated by the classes, subclasses, and speciesdisclosed herein. It will be appreciated that preferred subsetsdescribed for each variable herein can be used for any of the structuralsubsets as well. As used herein, the following definitions shall applyunless otherwise indicated.

As described herein, compounds of the invention may be optionallysubstituted with one or more substituents, such as are illustratedgenerally above, or as exemplified by particular classes, subclasses,and species of the invention. It will be appreciated that the phrase“optionally substituted” is used interchangeably with the phrase“substituted or unsubstituted.” In general, the term “substituted”,whether preceded by the term “optionally” or not, means that a hydrogenradical of the designated moiety is replaced with the radical of aspecified substituent, provided that the substitution results in astable or chemically feasible compound. The term “substitutable”, whenused in reference to a designated atom, means that attached to the atomis a hydrogen radical, which hydrogen atom can be replaced with theradical of a suitable substituent. Unless otherwise indicated, an“optionally substituted” group may have a substituent at eachsubstitutable position of the group, and when more than one position inany given structure may be substituted with more than one substituentselected from a specified group, the substituent may be either the sameor different at every position. Combinations of substituents envisionedby this invention are preferably those that result in the formation ofstable or chemically feasible compounds.

A stable compound or chemically feasible compound is one in which thechemical structure is not substantially altered when kept at atemperature from about −80° C. to about +40°, in the absence of moistureor other chemically reactive conditions, for at least a week, or acompound which maintains its integrity long enough to be useful fortherapeutic or prophylactic administration to a patient.

The phrase “one or more substituents”, as used herein, refers to anumber of substituents that equals from one to the maximum number ofsubstituents possible based on the number of available bonding sites,provided that the above conditions of stability and chemical feasibilityare met.

As used herein, the term “independently selected” means that the same ordifferent values may be selected for multiple instances of a givenvariable in a single compound.

As used herein, “a 3-7-membered saturated, partially unsaturated, oraromatic monocyclic ring having 0-3 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur, or an 8-10-membered partiallyunsaturated, or aromatic bicyclic ring system having 0-5 heteroatomsindependently selected from nitrogen, oxygen, or sulfur” includescycloaliphatic, heterocyclic, aryl and heteroaryl rings.

As used herein, the term “aromatic” includes aryl and heteroaryl groupsas described generally below and herein.

The term “aliphatic” or “aliphatic group”, as used herein, means anoptionally substituted straight-chain or branched C₁₋₁₂ hydrocarbon, ora cyclic C₁₋₁₂ hydrocarbon which is completely saturated or whichcontains one or more units of unsaturation, but which is not aromatic(also referred to herein as “carbocycle”, “cycloaliphatic”,“cycloalkyl”, or “cycloalkenyl”). For example, suitable aliphatic groupsinclude optionally substituted linear, branched or cyclic alkyl,alkenyl, alkynyl groups and hybrids thereof, such as (cycloalkyl)alkyl,(cycloalkenyl)alkyl, or (cycloalkyl)alkenyl. Unless otherwise specified,in various embodiments, aliphatic groups have 1-12, 1-10, 1-8, 1-6, 1-4,1-3, or 1-2 carbon atoms.

The term “alkyl”, used alone or as part of a larger moiety, refers to anoptionally substituted straight or branched chain hydrocarbon grouphaving 1-12, 1-10, 1-8, 1-6, 1-4, 1-3, or 1-2 carbon atoms.

The term “alkenyl”, used alone or as part of a larger moiety, refers toan optionally substituted straight or branched chain hydrocarbon grouphaving at least one double bond and having 2-12, 2-10, 2-8, 2-6, 2-4, or2-3 carbon atoms.

The term “alkynyl”, used alone or as part of a larger moiety, refers toan optionally substituted straight or branched chain hydrocarbon grouphaving at least one triple bond and having 2-12, 2-10, 2-8, 2-6, 2-4, or2-3 carbon atoms.

The terms “cycloaliphatic”, “carbocycle”, “carbocyclyl”, “carbocyclo”,or “carbocyclic”, used alone or as part of a larger moiety, refer to anoptionally substituted saturated or partially unsaturated cyclicaliphatic ring system having from 3 to about 14 ring carbon atoms. Insome embodiments, the cycloaliphatic group is an optionally substitutedmonocyclic hydrocarbon having 3-8 or 3-6 ring carbon atoms.Cycloaliphatic groups include, without limitation, optionallysubstituted cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl,cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, cyclooctyl,cyclooctenyl, or cyclooctadienyl. The terms “cycloaliphatic”,“carbocycle”, “carbocyclyl”, “carbocyclo”, or “carbocyclic” also includeoptionally substituted bridged or fused bicyclic rings having 6-12,6-10, or 6-8 ring carbon atoms, wherein any individual ring in thebicyclic system has 3-8 ring carbon atoms.

The term “cycloalkyl” refers to an optionally substituted saturated ringsystem of about 3 to about 10 ring carbon atoms. Exemplary monocycliccycloalkyl rings include cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, and cycloheptyl.

The term “cycloalkenyl” refers to an optionally substituted non-aromaticmonocyclic or multicyclic ring system containing at least onecarbon-carbon double bond and having about 3 to about 10 carbon atoms.Exemplary monocyclic cycloalkenyl rings include cyclopentyl,cyclohexenyl, and cycloheptenyl.

The terms “haloaliphatic”, “haloalkyl”, “haloalkenyl” and “haloalkoxy”refer to an aliphatic, alkyl, alkenyl or alkoxy group, as the case maybe, which is substituted with one or more halogen atoms. As used herein,the term “halogen” or “halo” means F, Cl, Br, or I. The term“fluoroaliphatic” refers to a haloaliphatic wherein the halogen isfluoro, including perfluorinated aliphatic groups. Examples offluoroaliphatic groups include, without limitation, fluoromethyl,difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2,2-trifluoroethyl,1,1,2-trifluoroethyl, 1,2,2-trifluoroethyl, and pentafluoroethyl.

The term “heteroatom” refers to one or more of oxygen, sulfur, nitrogen,phosphorus, or silicon (including, any oxidized form of nitrogen,sulfur, phosphorus, or silicon; the quaternized form of any basicnitrogen or; a substitutable nitrogen of a heterocyclic ring, forexample N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) orNR⁺ (as in N-substituted pyrrolidinyl)).

The terms “aryl” and “ar-”, used alone or as part of a larger moiety,e.g., “aralkyl”, “aralkoxy”, or “aryloxyalkyl”, refer to an optionallysubstituted C₆₋₁₄aromatic hydrocarbon moiety comprising one to threearomatic rings. Preferably, the aryl group is a C₆₋₁₀aryl group. Arylgroups include, without limitation, optionally substituted phenyl,naphthyl, or anthracenyl. The terms “aryl” and “ar-”, as used herein,also include groups in which an aryl ring is fused to one or morecycloaliphatic rings to form an optionally substituted cyclic structuresuch as a tetrahydronaphthyl, indenyl, or indanyl ring. The term “aryl”may be used interchangeably with the terms “aryl group”, “aryl ring”,and “aromatic ring”.

An “aralkyl” or “arylalkyl” group comprises an aryl group covalentlyattached to an alkyl group, either of which independently is optionallysubstituted. Preferably, the aralkyl group is C₆₋₁₀ arylC₁₋₆alkyl,including, without limitation, benzyl, phenethyl, and naphthylmethyl.

The terms “heteroaryl” and “heteroar-”, used alone or as part of alarger moiety, e.g., “heteroaralkyl”, or “heteroaralkoxy”, refer togroups having 5 to 14 ring atoms, preferably 5, 6, 9, or 10 ring atoms;having 6, 10, or 14 π electrons shared in a cyclic array; and having, inaddition to carbon atoms, from one to five heteroatoms. A heteroarylgroup may be mono-, bi-, tri-, or polycyclic, preferably mono-, bi-, ortricyclic, more preferably mono- or bicyclic. The term “heteroatom”refers to nitrogen, oxygen, or sulfur, and includes any oxidized form ofnitrogen or sulfur, and any quaternized form of a basic nitrogen. Forexample, a nitrogen atom of a heteroaryl may be a basic nitrogen atomand may also be optionally oxidized to the corresponding N-oxide. When aheteroaryl is substituted by a hydroxy group, it also includes itscorresponding tautomer. The terms “heteroaryl” and “heteroar-”, as usedherein, also include groups in which a heteroaromatic ring is fused toone or more aryl, cycloaliphatic, or heterocycloaliphatic rings.Nonlimiting examples of heteroaryl groups include thienyl, furanyl,pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl,isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl,pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl,naphthyridinyl, pteridinyl, indolyl, isoindolyl, benzothienyl,benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl,quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl,quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl,phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl,tetrahydroisoquinolinyl, and pyrido[2,3-b]-1,4-oxazin-3(4H)-one. Theterm “heteroaryl” may be used interchangeably with the terms “heteroarylring”, “heteroaryl group”, or “heteroaromatic”, any of which termsinclude rings that are optionally substituted. The term “heteroaralkyl”refers to an alkyl group substituted by a heteroaryl, wherein the alkyland heteroaryl portions independently are optionally substituted.

As used herein, the terms “heterocycle”, “heterocyclyl”, “heterocyclicradical”, and “heterocyclic ring” are used interchangeably and refer toa stable 3- to 8-membered monocyclic or 7-10-membered bicyclicheterocyclic moiety that is either saturated or partially unsaturated,and having, in addition to carbon atoms, one or more, preferably one tofour, heteroatoms, as defined above. When used in reference to a ringatom of a heterocycle, the term “nitrogen” includes a substitutednitrogen. As an example, in a saturated or partially unsaturated ringhaving 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, thenitrogen may be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as inpyrrolidinyl), or NR⁺ (as in N-substituted pyrrolidinyl).

A heterocyclic ring can be attached to its pendant group at anyheteroatom or carbon atom that results in a stable structure and any ofthe ring atoms can be optionally substituted. Examples of such saturatedor partially unsaturated heterocyclic radicals include, withoutlimitation, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl,decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl,diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and thiamorpholinyl. Aheterocyclyl group may be mono-, bi-, tri-, or polycyclic, preferablymono-, bi-, or tricyclic, more preferably mono- or bicyclic. The term“heterocyclylalkyl” refers to an alkyl group substituted by aheterocyclyl, wherein the alkyl and heterocyclyl portions independentlyare optionally substituted. Additionally, a heterocyclic ring alsoincludes groups in which the heterocyclic ring is fused to one or morearyl rings.

As used herein, the term “partially unsaturated” refers to a ring moietythat includes at least one double or triple bond between ring atoms. Theterm “partially unsaturated” is intended to encompass rings havingmultiple sites of unsaturation, but is not intended to include aromatic(e.g., aryl or heteroaryl) moieties, as herein defined.

The term “alkylene” refers to a bivalent alkyl group. An “alkylenechain” is a polymethylene group, i.e., —(CH₂)_(n)—, wherein n is apositive integer, preferably from 1 to 6, from 1 to 4, from 1 to 3, from1 to 2, or from 2 to 3. An optionally substituted alkylene chain is apolymethylene group in which one or more methylene hydrogen atoms isoptionally replaced with a substituent. Suitable substituents includethose described below for a substituted aliphatic group and also includethose described in the specification herein. It will be appreciated thattwo substituents of the alkylene group may be taken together to form aring system. In certain embodiments, two substituents can be takentogether to form a 3-7-membered ring. The substituents can be on thesame or different atoms.

An alkylene chain also can be optionally interrupted by a functionalgroup. An alkylene chain is “interrupted” by a functional group when aninternal methylene unit is interrupted by the functional group. Examplesof suitable “interrupting functional groups” are described in thespecification and claims herein.

For purposes of clarity, all bivalent groups described herein,including, e.g., the alkylene chain linkers described above, areintended to be read from left to right, with a correspondingleft-to-right reading of the formula or structure in which the variableappears.

An aryl (including aralkyl, aralkoxy, aryloxyalkyl and the like) orheteroaryl (including heteroaralkyl and heteroarylalkoxy and the like)group may contain one or more substituents and thus may be “optionallysubstituted”. In addition to the substituents defined above and herein,suitable substituents on the unsaturated carbon atom of an aryl orheteroaryl group also include and are generally selected from -halo,—NO₂, —CN, —R⁺, —C(R⁺)═C(R⁺)₂, —C≡C—R⁺, —OR⁺, —SR^(o), —S(O)R^(o),—SO₂R^(o), —SO₃R⁺, —SO₂N(R⁺)₂, —N(R⁺)₂, —NR⁺C(O)R⁺, —NR⁺C(S)R⁺,—NR⁺C(O)N(R⁺)₂, —NR⁺C(S)N(R⁺)₂, —N(R⁺)C(═NR⁺)—N(R⁺)₂,—N(R⁺)C(═NR⁺)—R^(o), —NR⁺CO₂R⁺, —NR⁺SO₂R^(o), —NR⁺SO₂N(R⁺)₂, —O—C(O)R⁺,—O—CO₂R⁺, —OC(O)N(R⁺)₂, —C(O)R⁺, —C(S)R^(o), —CO₂R⁺, —C(O)—C(O)R⁺,—C(O)N(R⁺)₂, —C(S)N(R⁺)₂, —C(O)N(R⁺)—OR⁺, —C(O)N(R⁺)C(═NR⁺)—N(R⁺)₂,—N(R⁺)C(═NR⁺)—N(R⁺)—C(O)R⁺, —C(═NR⁺)—N(R⁺)₂, —C(═NR⁺)—OR⁺,—N(R⁺)—N(R⁺)₂, —C(═NR⁺)—N(R⁺)—OR⁺, —C(R^(o))═N—OR⁺, —P(O)(R⁺)₂,—P(O)(OR⁺)₂, —O—P(O)—OR⁺, and —P(O)(NR⁺)—N(R⁺)₂, wherein R⁺,independently, is hydrogen or an optionally substituted aliphatic, aryl,heteroaryl, cycloaliphatic, or heterocyclyl group, or two independentoccurrences of R⁺ are taken together with their intervening atom(s) toform an optionally substituted 5-7-membered aryl, heteroaryl,cycloaliphatic, or heterocyclyl ring. Each R^(o) is an optionallysubstituted aliphatic, aryl, heteroaryl, cycloaliphatic, or heterocyclylgroup.

An aliphatic or heteroaliphatic group, or a non-aromatic carbycyclic orheterocyclic ring may contain one or more substituents and thus may be“optionally substituted”. Unless otherwise defined above and herein,suitable substituents on the saturated carbon of an aliphatic orheteroaliphatic group, or of a non-aromatic carbocyclic or heterocyclicring are selected from those listed above for the unsaturated carbon ofan aryl or heteroaryl group and additionally include the following: ═O,═S, ═C(R*)₂, ═N—N(R*)₂, ═N—OR*, ═N—NHC(O)R*, ═N—NHCO₂R^(o)═N—NHSO₂R^(o)or ═N—R* where R^(o) is defined above, and each R* is independentlyselected from hydrogen or an optionally substituted C₁₋₆ aliphaticgroup.

In addition to the substituents defined above and herein, optionalsubstituents on the nitrogen of a non-aromatic heterocyclic ring alsoinclude and are generally selected from R⁺, —N(R⁺)₂, —C(O)R⁺, —C(O)OR⁺,—C(O)C(O)R⁺, —C(O)CH₂C(O)R⁺, —S(O)₂R⁺, —S(O)₂N(R⁺)₂, —C(S)N(R⁺)₂,—C(═NH)—N(R⁺)₂, or —N(R⁺)S(O)₂R⁺; wherein each R⁺ is defined above. Aring nitrogen atom of a heteroaryl or non-aromatic heterocyclic ringalso may be oxidized to form the corresponding N-hydroxy or N-oxidecompound. A nonlimiting example of such a heteroaryl having an oxidizedring nitrogen atom is N-oxidopyridyl.

As detailed above, in some embodiments, two independent occurrences ofR⁺ (or any other variable similarly defined in the specification andclaims herein), are taken together with their intervening atom(s) toform a monocyclic or bicyclic ring selected from 3-13-memberedcycloaliphatic, 3-12-membered heterocyclyl having 1-5 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, 6-10-memberedaryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur.

Exemplary rings that are formed when two independent occurrences of R⁺(or any other variable similarly defined in the specification and claimsherein), are taken together with their intervening atom(s) include, butare not limited to the following: a) two independent occurrences of R⁺(or any other variable similarly defined in the specification or claimsherein) that are bound to the same atom and are taken together with thatatom to form a ring, for example, N(R⁺)₂, where both occurrences of R⁺are taken together with the nitrogen atom to form a piperidin-1-yl,piperazin-1-yl, or morpholin-4-yl group; and b) two independentoccurrences of R⁺ (or any other variable similarly defined in thespecification or claims herein) that are bound to different atoms andare taken together with both of those atoms to form a ring, for examplewhere a phenyl group is substituted with two occurrences of OR⁺

these two occurrences of R⁺ are taken together with the oxygen atoms towhich they are bound to form a fused 6-membered oxygen containing ring:

It will be appreciated that a variety of other rings (e.g., spiro andbridged rings) can be formed when two independent occurrences of R⁺ (orany other variable similarly defined in the specification and claimsherein) are taken together with their intervening atom(s) and that theexamples detailed above are not intended to be limiting.

Exemplary rings that are formed when two independent occurrences ofR^(3′) or R⁴ are taken together with their intervening atom(s) include,but are not limited to the following: indolizinyl, imidazopyridyl,indolyl, isoindolyl, indazolyl, benzimidazolyl, benzthiazolyl,benzoxazolyl, 4H-furo[3,2-b]pyrrolyl, pyrazolopyrimidinyl, purinyl, andpyrrolizinyl

Exemplary rings that are formed when two independent occurrences of R⁷,R^(7a), or R^(7b) are taken together with their intervening atom(s)include, but are not limited to the following: cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl,cyclohexenyl, cycloheptenyl, cyclooctenyl, tetrahydrofuranyl,tetrahydropyranyl, tetrahydrothienyl, pyrrolidinyl, pyrrolidonyl,piperidinyl, pyrrolinyl, oxazolidinyl, piperazinyl, dioxanyl, furanyl,thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyranyl, pyridyl,pyrimidinyl, pyrazinyl, triazinyl, morpholinyl, and thiomorpholinyl.

Exemplary rings that are formed when two independent occurrences ofR^(7a) and R², or R^(7b) and R² are taken together with theirintervening atom(s) include, but are not limited to the following:isoindolyl, indazolyl, benzothienyl, dihydrobenzothienyl,isobenzofuranyl, benzoisoxazolyl, dihydroisobenzofuranyl,pyrazolopyrimidinyl, pyrazolopyridinyl, isoquinolyl,tetrahydroisoquinolinyl, phthalazinyl, isochromanyl, isothiochromanyl,isoindolinyl, and benzoisothiazolyl.

Exemplary rings that are formed when two independent occurrences of X₄and X₅, or X₆ and X₇; are taken together with their intervening atom(s)include, but are not limited to the following: pyrazolopyrimidinyl,purinyl, quinolyl, tetrahydroquinolinyl, quinazolinyl, naphthyridinyl,pyridopyrimidinyl, pyrazolopyridinyl, pyrrolopyridinyl,pyrrolopyrimidinyl, imidazopyridinyl,1H-pyrrolo[2,3-b]pyridinyl-2(3H)-one,3,4-dihydro-1,8-naphthyridinyl-2(1H)-one, 1,8-naphthyridinyl-2(1H)-one,1H-pyridyl[2,3-d][1,3]oxazin-2(4H)-one,1H-imidazo[4,5-b]pyridyl-2(3H)-one, oxazolo[4,5-b]pyridyl-2(3H)-one,1,2-dihydropyridyl[2,3-b]pyrazin-3(4H)-one,2H-pyridyl[3,2-h][1,4]oxazin-3(4H)-one,3,4-dihydropyridyl[2,3-d]pyrimidin-2(1H)-one, imidazopyridinyl, andtetrahydroquinazolinyl.

Exemplary rings that are formed when two independent occurrences of Y₁and Q₁, Y₃ and Q₂, or Y₄ and Y₅ are taken together with theirintervening atom(s) include, but are not limited to the following:indolyl, indazolyl, 4H-furo[3,2-b]pyrrolyl, 4H-thieno[3,2-b]pyrrolyl,5H-furo[2,3-b]pyrrolyl, 5H-thieno[2,3-b]pyrrolyl,pyrrolo[3,4-b]pyrrolyl, pyrrolo[3,2-b]pyrrolyl, pyrrolo[2,3-b]pyrrolyl,dihydropyrrolo[3,2-b]pyrrolyl, dihydropyrrolo[2,3-b]pyrrolyl,5H-pyrrolo[3,2-d]oxazole, 5H-pyrrolo[3,2-d]thiazole, pyrrolopyrimidinyl,pyrrolopyridinyl, pyrazolopyrimidinyl and pyrazolopyridinyl.

Unless otherwise stated, structures depicted herein are also meant toinclude all isomeric (e.g., enantiomeric, diastereomeric, and geometric(or conformational)) forms of the structure; for example, the R and Sconfigurations for each asymmetric center, (Z) and (E) double bondisomers, and (Z) and (E) conformational isomers. Therefore, singlestereochemical isomers as well as enantiomeric, diastereomeric, andgeometric (or conformational) mixtures of the present compounds arewithin the scope of the invention. Unless otherwise stated, alltautomeric forms of the compounds of the invention are within the scopeof the invention. Additionally, unless otherwise stated, structuresdepicted herein are also meant to include compounds that differ only inthe presence of one or more isotopically enriched atoms. For example,compounds having the present structures where there is a replacement ofhydrogen by deuterium or tritium, or a replacement of a carbon by a ¹³C-or ¹⁴C-enriched carbon are within the scope of this invention. Suchcompounds are useful, as a nonlimiting example, as analytical tools orprobes in biological assays.

It is to be understood that, when a disclosed compound has at least onechiral center, the present invention encompasses one enantiomer ofinhibitor free from the corresponding optical isomer, racemic mixture ofthe inhibitor and mixtures enriched in one enantiomer relative to itscorresponding optical isomer. When a mixture is enriched in oneenantiomer relative to its optical isomers, the mixture contains, forexample, an enantiomeric excess of at least 50%, 75%, 90%, 95% 99% or99.5%.

The enantiomers of the present invention may be resolved by methodsknown to those skilled in the art, for example by formation ofdiastereoisomeric salts which may be separated, for example, bycrystallization; formation of diastereoisomeric derivatives or complexeswhich may be separated, for example, by crystallization, gas-liquid orliquid chromatography; selective reaction of one enantiomer with anenantiomer-specific reagent, for example enzymatic esterification; orgas-liquid or liquid chromatography in a chiral environment, for exampleon a chiral support for example silica with a bound chiral ligand or inthe presence of a chiral solvent. Where the desired enantiomer isconverted into another chemical entity by one of the separationprocedures described above, a further step is required to liberate thedesired enantiomeric form. Alternatively, specific enantiomers may besynthesized by asymmetric synthesis using optically active reagents,substrates, catalysts or solvents, or by converting one enantiomer intothe other by asymmetric transformation.

When a disclosed compound has at least two chiral centers, the presentinvention encompasses a diastereomer free of other diastereomers, a pairof diastereomers free from other diasteromeric pairs, mixtures ofdiasteromers, mixtures of diasteromeric pairs, mixtures of diasteromersin which one diastereomer is enriched relative to the otherdiastereomer(s) and mixtures of diasteromeric pairs in which onediastereomeric pair is enriched relative to the other diastereomericpair(s). When a mixture is enriched in one diastereomer ordiastereomeric pair(s) relative to the other diastereomers ordiastereomeric pair(s), the mixture is enriched with the depicted orreferenced diastereomer or diastereomeric pair(s) relative to otherdiastereomers or diastereomeric pair(s) for the compound, for example,by a molar excess of at least 50%, 75%, 90%, 95%, 99% or 99.5%.

The diastereoisomeric pairs may be separated by methods known to thoseskilled in the art, for example chromatography or crystallization andthe individual enantiomers within each pair may be separated asdescribed above. Specific procedures for chromatographically separatingdiastereomeric pairs of precursors used in the preparation of compoundsdisclosed herein are provided the examples herein.

3. Description of Exemplary Compounds

In certain embodiments, for compounds of general formula IA, IA-a, IB orIB-a, CY is:

In certain embodiments, for compounds of general formula IA, IA-a, IB orIB-a X₁ is N, G₂ is —N(R^(3′))—, and X₂ and X₃ are CH. In certain otherembodiments, X₁ and X₂ are N, G₂ is —N(R^(3′))—, and X₃ is CH. Incertain other embodiments, X₃ is N, G₂ is —N(R^(3′))—, and X₁ and X₂ areCH. In certain other embodiments, X₁ is N, X₂ is CH, X₃ is N(R^(3′))-and G₂ is ═N—.

In certain embodiments, for compounds of general formula IA, IA-a, IB orIB-a HY is selected from:

wherein each occurrence of X₅, X₆, and X₇ is independently CR¹⁰ or N,provided no more than two occurrences of X₅, X₆, and X₇ are N;

each occurrence of Q₁ and Q₂ is independently S, O or —NR⁵;

each occurrence of Y₁ and Y₇ is independently —CR¹⁰ or N;

-   -   or wherein two adjacent occurrences of X₆ and X₇, or Y₁ and Q₁,        taken together with the atom to which they are bound, form an        optionally substituted fused group selected from 5-6-membered        aryl, or 5-6-membered heteroaryl having 1-5 heteroatoms        independently selected from nitrogen, oxygen, or sulfur.

In certain embodiments, for compounds of general formula IA, IA-a, IB orIB-a HY is selected from:

-   -   wherein each HY group is optionally additionally substituted        with one or more occurrences of R¹⁰, and        in xviii represents a single bond or a double bond.

In certain embodiments, for compounds of general formula IA, IA-a, IB orIB-a HY is selected from:

-   -   wherein each HY group is optionally additionally substituted        with one or more occurrences of R¹⁰, and        in xviii represents a single bond or a double bond.

In yet other embodiments, for compounds of general formula IA, IA-a, IBor IB-a G₁ is C(R⁸). In other embodiments, G₁ is CH.

In still other embodiments, G₁ is N.

In certain embodiments, for compounds of general formula IA, IA-a, IB orIB-a, W is —C(R⁷)₂—, wherein one occurrence of R⁷ is hydrogen and theother occurrence of R⁷ is hydrogen, optionally substituted C₁₋₆aliphatic, —N(R^(7b))₂, —OR^(7a), —SR^(7a), halo, or —CN; and whereineach occurrence of R^(7a) is independently hydrogen or optionallysubstituted C₁₋₆ aliphatic; and each occurrence of R^(7b) isindependently hydrogen, optionally substituted C₁₋₆ aliphatic,—C(O)R^(7a), or —S(O)₂R^(7a); or wherein two occurrences of R^(7b),taken together with the nitrogen atom to which they are bound, form anoptionally substituted 3-6-membered heterocyclic ring.

In certain embodiments, for compounds of general formula IA, IA-a, IB orIB-a W is C(H)(N(R^(7b))₂)—, —CH₂—, —C(H)(OR^(7a))—, —NR^(7b)—, orN(R^(7a))C(O)—, wherein each occurrence of R^(7a) is independentlyhydrogen or optionally substituted C₁₋₆ aliphatic; and each occurrenceof R^(7b) is independently hydrogen or optionally substituted C₁₋₆aliphatic.

In certain embodiments, for compounds of general formula IA, IA-a, IB orIB-a Ring A is 6-10-membered aryl or 5-10-membered heteroaryl having 1-5heteroatoms independently selected from nitrogen, oxygen, or sulfur; andn is 0 to 3.

In other embodiments, ring A is a group selected from:

wherein ring A is optionally further substituted by n occurrences of R²,and wherein R² is hydrogen or an optionally substituted group selectedfrom C₁₋₆aliphatic, 3-10-membered cycloaliphatic, 4-10-memberedheterocyclyl having 1-5 heteroatoms independently selected fromnitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-memberedheteroaryl having 1-5 heteroatoms independently selected from nitrogen,oxygen, or sulfur.

In certain other embodiments, for compounds of general formula IA, IA-a,IB or IB-a, Ring A is a group selected from:

wherein ring A is optionally further substituted by n occurrences of R²,and wherein R² is hydrogen or an optionally substituted group selectedfrom C₁₋₆aliphatic, 3-10-membered cycloaliphatic, 4-10-memberedheterocyclyl having 1-5 heteroatoms independently selected fromnitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-memberedheteroaryl having 1-5 heteroatoms independently selected from nitrogen,oxygen, or sulfur.

In still other embodiments, ring A is a naphthyl group; each occurrenceof R² is independently halogen, C₁₋₃ alkyl, —CN, C₁₋₃ haloalkyl, —OC₁₋₃alkyl, —OC₁₋₃ haloalkyl, —NHC(O)C₁₋₃ alkyl, —NHC(O)NHC₁₋₃ alkyl,—NHS(O)₂C₁₋₃ alkyl, or —C(O)H; and n is 0 to 3.

In still other embodiments, ring A is a naphthyl group, R² is halogenand n is 1 to 2. In yet other embodiments, ring A is a naphthyl groupand n is 0. In yet other embodiments, Ring A is a phenyl group, R² ishalogen and n is 1 to 2.

In certain embodiments, for compounds of general formula IA, IA-a, IB orIB-a Ring A is a phenyl group; each occurrence of R² is independentlyhalogen, C₁₋₃ alkyl, —CN, C₁₋₃ haloalkyl, —OC₁₋₃ alkyl, —OC₁₋₃haloalkyl, —NHC(O)C₁₋₃ alkyl, —NHC(O)NHC₁₋₃ alkyl, —NHS(O)₂C₁₋₃ alkyl,or —C(O)H; and n is 0 to 3.

In still other embodiments, Ring A is a phenyl group, R² is halogen andn is 1 to 2.

In still other embodiments, a compound having the structure of formulaII is provided:

wherein:

X₄, X₅ and X₆ are each independently —CR¹⁰ or N, provided no more thantwo occurrences of X₄, X₅ and X₆ are N;

or two adjacent groups selected from R¹⁰, X₄, X₅, and X₆, takentogether, form an optionally substituted group selected from3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-5heteroatoms independently selected from nitrogen, oxygen, or sulfur,6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatomsindependently selected from nitrogen, oxygen, or sulfur.

In some embodiments, for compounds of formula II, one of X⁴, X⁵, or X⁶is N.

In still other embodiments, for compounds of formula II, all of X⁴, X⁵,or X⁶ are CR¹⁰.

In other embodiments, for compounds of formula II, each occurrence ofR¹⁰ is independently selected from —CN, —OR^(10a), —N(R¹¹)₂, halogen,C₁₋₄alkyl, —N(R¹¹)COR^(10a), or wherein two occurrences of R¹⁰, takentogether with the atoms to which they are bound form an optionallysubstituted group selected from a fused 5- or 6-membered cycloaliphatic,4-10-membered heterocyclyl, 6-10-membered aryl or 5-10-memberedheteroaryl ring, wherein the heterocyclyl and heteroaryl rings have 1-3heteroatoms independently selected from nitrogen, oxygen, or sulfur.

In some other embodiments, for compounds of formula II, CY is

In some other embodiments, for compounds of formula II, X₁ is N, G₂ is—N(R^(3′))—, and X₂ and X₃ are CH.

In some other embodiments, for compounds of formula II, X₁ and X₂ are N,G₂ is —N(R^(3′))—, and X₃ is CH.

In some other embodiments, for compounds of formula II, X₃ is N, G₂ is—N(R^(3′))—, and X₁ and X₂ are CH.

In some other embodiments, for compounds of formula II, X₁ is N, X₂ isCH, X₃ is N(R^(3′))- and G₂ is ═N—.

In some other embodiments, for compounds of formula II, Ring A is anoptionally substituted 6-10-membered aryl or 5-10-membered heteroarylhaving 1-5 heteroatoms independently selected from nitrogen, oxygen, orsulfur; and n is 0 to 3.

In other embodiments, for compounds of formula II, ring A is a groupselected from:

wherein ring A is optionally further substituted by n occurrences of R²,and wherein R² is hydrogen or an optionally substituted group selectedfrom C₁₋₆aliphatic, 3-10-membered cycloaliphatic, 4-10-memberedheterocyclyl having 1-5 heteroatoms independently selected fromnitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-memberedheteroaryl having 1-5 heteroatoms independently selected from nitrogen,oxygen, or sulfur.

In certain other embodiments, for compounds of general formula II, RingA is a group selected from

wherein ring A is optionally further substituted by n occurrences of R²,and wherein R² is hydrogen or an optionally substituted group selectedfrom C₁₋₆aliphatic, 3-10-membered cycloaliphatic, 4-10-memberedheterocyclyl having 1-5 heteroatoms independently selected fromnitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-memberedheteroaryl having 1-5 heteroatoms independently selected from nitrogen,oxygen, or sulfur.

In still other embodiments, ring A is a naphthyl group; each occurrenceof R² is independently halogen, C₁₋₃ alkyl, —CN, C₁₋₃ haloalkyl, —OC₁₋₃alkyl, —OC₁₋₃ haloalkyl, —NHC(O)C₁₋₃ alkyl, —NHC(O)NHC₁₋₃ alkyl,—NHS(O)₂C₁₋₃ alkyl, or —C(O)H; and n is 0 to 3.

In still other embodiments, ring A is a naphthyl group, R² is halogenand n is 1 to 2. In yet other embodiments, ring A is a naphthyl groupand n is 0. In yet other embodiments, Ring A is a phenyl group, R² ishalogen and n is 1 to 2.

In some other embodiments, for compounds of formula II, Ring A is aphenyl group optionally substituted with 1-3 independent occurrences ofhalogen, C₁₋₃ alkyl, —CN, C₁₋₃haloalkyl, —OC₁₋₃ alkyl, —OC₁₋₃haloalkyl,—NHC(O)C₁₋₃ alkyl, —NHC(O)NHC₁₋₃ alkyl, NHS(O)₂C₁₋₃ alkyl, or —C(O)H;and n is 0 to 3.

In still other embodiments, Ring A is a phenyl group, R² is halogen andn is 1 to 2.

In some other embodiments, for compounds of formula II, W is —C(R⁷)₂—,wherein one occurrence of R⁷ is hydrogen and the other occurrence of R⁷is selected from hydrogen, optionally substituted C₁₋₄ aliphatic,—N(R^(7b))₂, —OR^(7a), —SR^(7a), halo, or —CN; and

-   -   wherein each occurrence of R^(7a) is independently hydrogen or        optionally substituted C₁₋₆ aliphatic;    -   each occurrence of R^(7b) is independently hydrogen, optionally        substituted C₁₋₆ aliphatic, —C(O)R^(7a), or —S(O)₂R^(7a); or    -   wherein any two occurrences of R⁷, R^(7a), or R^(7b) taken        together with the atom to which they are bound, form an        optionally substituted group selected from a 3-6-membered        cycloaliphatic ring, 6-10-membered aryl, 3-6-membered        heterocyclyl having 1-5 heteroatoms independently selected from        nitrogen, oxygen, or sulfur, or 5-10-membered heteroaryl having        1-5 heteroatoms independently selected from nitrogen, oxygen, or        sulfur; or any two occurrences of R^(7a) and R², or R^(7b) and        R² taken together with the nitrogen atom to which they are        bound, form an optionally substituted group selected from        3-6-membered heterocyclyl having 1-5 heteroatoms independently        selected from nitrogen, oxygen, or sulfur, or 5-10-membered        heteroaryl having 1-5 heteroatoms independently selected from        nitrogen, oxygen, or sulfur.

In some other embodiments, for compounds of formula II, W is—C(H)(N(R^(7b))₂)—, —CH₂—, —C(H)(OR^(7a))—, —NR^(7b)—, orN(R^(7a))C(O)—, wherein each occurrence of R^(7a) is independentlyhydrogen or optionally substituted C₁₋₆ aliphatic; and each occurrenceof R^(7b) is independently hydrogen or optionally substituted C₁₋₆aliphatic.

In still other embodiments, a compound having the structure of formulaIII is provided:

wherein R^(10d) is hydrogen or optionally substituted C₁₋₄alkyl, andR^(10e) is R¹⁰.

In some other embodiments, for compounds of formula III, R^(10e) is-T₁-R^(10b) or hydrogen.

In still other embodiments, for compounds of formula III, R^(10e) ishydrogen, —CH₂N(R¹¹)₂, or —CH₂N(R¹¹)C(═NR¹¹)N(R¹¹)₂, wherein R¹¹ is—C(O)R^(11a), an optionally substituted group selected from C₁₋₆aliphatic, 3-10-membered cycloaliphatic, 4-10-membered heterocyclylhaving 1-5 heteroatoms independently selected from nitrogen, oxygen orsulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5heteroatoms independently selected from nitrogen, oxygen, or sulfur.

In some other embodiments, for compounds of formula III, R¹¹ is anoptionally substituted C₁₋₆ aliphatic group, the C₁₋₆ aliphatic group isfurther defined as (CH₂)_(x)R^(11b) or —(CH₂)_(x)N(R^(11b))₂,—(CH₂)_(x)N(R^(11b))C(O)R^(11b), or (CH₂)_(x)N(R^(11b))C(O)OR^(11b),wherein R^(11b) is hydrogen or an optionally substituted group selectedfrom C₁₋₆ aliphatic, 3-10-membered cycloaliphatic, 4-10-memberedheterocyclyl having 1-5 heteroatoms independently selected fromnitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-memberedheteroaryl having 1-5 heteroatoms independently selected from nitrogen,oxygen, or sulfur; and x is 1 to 3.

In some other embodiments, for compounds of formula III, X₁ is N, and X₂and X₃ are CH.

In some other embodiments, for compounds of formula III, X₁ and X₂ areN, and X₃ is CH.

In some other embodiments, for compounds of formula III, X₃ is N, and X₁and X₂ are CH.

In some other embodiments, for compounds of formula III, Ring A is anoptionally substituted 6-10-membered aryl or 5-10-membered heteroarylhaving 1-5 heteroatoms independently selected from nitrogen, oxygen, orsulfur; and n is 0 to 3.

In other embodiments, ring A is a group selected from:

wherein ring A is optionally further substituted by n occurrences of R²,and wherein R² is hydrogen or an optionally substituted group selectedfrom C₁₋₆aliphatic, 3-10-membered cycloaliphatic, 4-10-memberedheterocyclyl having 1-5 heteroatoms independently selected fromnitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-memberedheteroaryl having 1-5 heteroatoms independently selected from nitrogen,oxygen, or sulfur.

In certain other embodiments, for compounds of general formula III, RingA is a group selected from:

wherein ring A is optionally further substituted by n occurrences of R²,and wherein R^(2a) is hydrogen or an optionally substituted groupselected from C₁₋₆aliphatic, 3-10-membered cycloaliphatic, 4-10-memberedheterocyclyl having 1-5 heteroatoms independently selected fromnitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-memberedheteroaryl having 1-5 heteroatoms independently selected from nitrogen,oxygen, or sulfur.

In still other embodiments, ring A is a naphthyl group; each occurrenceof R² is independently halogen, C₁₋₃ alkyl, —CN, C₁₋₃ haloalkyl, —OC₁₋₃alkyl, —OC₁₋₃ haloalkyl, —NHC(O)C₁₋₃ alkyl, —NHC(O)NHC₁₋₃ alkyl,—NHS(O)₂C₁₋₃ alkyl, or —C(O)H; and n is 0 to 3.

In still other embodiments, ring A is a naphthyl group, R² is halogenand n is 1 to 2. In yet other embodiments, ring A is a naphthyl groupand n is 0. In yet other embodiments, Ring A is a phenyl group, R² ishalogen and n is 1 to 2.

In some other embodiments, for compounds of formula III, Ring A is aphenyl group optionally substituted with 1-3 independent occurrences ofhalogen, C₁₋₃ alkyl, —CN, C₁₋₃haloalkyl, —OC₁₋₃ alkyl, —OC₁₋₃haloalkyl,—NHC(O)C₁₋₃ alkyl, —NHC(O)NHC₁₋₃ alkyl, —NHS(O)₂C₁₋₃ alkyl, or —C(O)H;and n is 0 to 3.

In some other embodiments, Ring A is a phenyl group, R² is halogen and nis 1 to 2.

In some other embodiments, for compounds of formula III, W is —C(R⁷)₂—,wherein one occurrence of R⁷ is hydrogen and the other occurrence of R⁷is selected from hydrogen, optionally substituted C₁₋₄ aliphatic,—N(R^(7b))₂, —OR^(7a), —SR^(7a), halo, or —CN; and

-   -   wherein each occurrence of R^(7a) is independently hydrogen or        optionally substituted C₁₋₆ aliphatic;    -   each occurrence of R^(7b) is independently hydrogen, optionally        substituted C₁₋₆ aliphatic, —C(O)R^(7a), or —S(O)₂R^(7a); or    -   wherein any two occurrences of R⁷, R^(7a), or R^(7b) taken        together with the atom to which they are bound, form an        optionally substituted group selected from a 3-6-membered        cycloaliphatic ring, 6-10-membered aryl, 3-6-membered        heterocyclyl having 1-5 heteroatoms independently selected from        nitrogen, oxygen, or sulfur, or 5-10-membered heteroaryl having        1-5 heteroatoms independently selected from nitrogen, oxygen, or        sulfur; or        any two occurrences of R^(7a) and R², or R^(7b) and R² taken        together with the nitrogen atom to which they are bound, form an        optionally substituted group selected from 3-6-membered        heterocyclyl having 1-5 heteroatoms independently selected from        nitrogen, oxygen, or sulfur, or 5-10-membered heteroaryl having        1-5 heteroatoms independently selected from nitrogen, oxygen, or        sulfur.

In some other embodiments, for compounds of formula III, W is—C(H)(N(R^(7b))₂)—, —CH₂—, —C(H)(OR^(7a))—, —NR^(7b)—, or—N(R^(7a))C(O)—, wherein each occurrence of R^(7a) is independentlyhydrogen or optionally substituted C₁₋₆ aliphatic; and each occurrenceof R^(7b) is independently hydrogen or optionally substituted C₁₋₆aliphatic.

In certain embodiments, for compounds of general formula IA-a, IB-a, IA,IB, II or III, CY is:

In certain embodiments, for compounds of general formula IA-a, IB-a, IA,IB, II or III, X₈ and X₁₁ are N, X₉ and X₁₀ are CR⁴, and Y₁₁ is O.

In certain embodiments, for compounds of general formula IA-a, IB-a, IA,IB, II or III, HY is selected from:

wherein each HY group is optionally additionally substituted with one ormore occurrences of R¹⁴.

In yet other embodiments, for compounds of general formula IA-a, IB-a,IA, IB, II or III, G₁ is N.

In still other embodiments, for compounds of general formula IA-a, IB-a,IA, IB, II or III, R¹ is —C(O)OH.

In certain other embodiments, for compounds of general formula IA-i-a,IB-i-a, IA-i, or IB-i,

R³ is H. In certain other embodiments, R³ is C₁₋₆ aliphatic. In certainembodiments, R³ is C₁₋₄ alkyl. In certain embodiments, R³ is methyl orethyl.

In certain embodiments, for compounds of general formula IA-i-a, IB-i-a,IA-i, or IB-i, G₁ is N. In certain other embodiments, G₁ is C(R⁸). Incertain embodiments, G₁ is C(R⁸) and R⁸ is —CN, halogen, or C₁₋₆aliphatic. In certain embodiments, R⁸ is C₁₋₄ alkyl, C₂₋₄ alkenyl, orC₂₋₄ alkynyl. In certain embodiments, R⁸ is CN or C₂₋₄ alkynyl.

In certain embodiments, for compounds of general formula IA-i-a, IB-i-a,IA-i, or IB-i, HY is selected from:

In certain embodiments, HY is

wherein each occurrence of m is 1 and q is 0 or 1. In certainembodiments, q is 0.

In certain embodiments, HY is

wherein m and p are 1 and q is 0 or 1. In certain embodiments, q is 0.

In certain embodiments, for compounds of general formula IA-i-a, IB-i-a,IA-i, or IB-i W is —C(R⁷)₂—, wherein one occurrence of R⁷ is hydrogenand the other occurrence of R⁷ is hydrogen, optionally substituted C₁₋₆aliphatic, —N(R^(7b))₂, or F; and each occurrence of R^(7b) isindependently hydrogen, optionally substituted C₁₋₆ aliphatic,—C(O)R^(7a), or —S(O)₂R^(7a); or wherein two occurrences of R^(7b),taken together with the nitrogen atom to which they are bound, form anoptionally substituted 3-6-membered heterocyclic ring; and wherein eachoccurrence of R^(7a) is independently hydrogen or optionally substitutedC₁₋₆ aliphatic.

In certain embodiments, for compounds of general formula IA-i-a, IB-i-a,IA-i, or IB-i W is —C(H)(N(R^(7b))₂)— or —CH₂—, wherein each occurrenceof R^(7b) is independently hydrogen or optionally substituted C₁₋₆aliphatic.

In certain embodiments, for compounds of general formula IA-i-a, IB-i-a,IA-i, or IB-i W is a covalent bond.

In certain embodiments, for compounds of general formula IA-i-a, IB-i-a,IA-i, or IB-i Ring A is 6-10-membered aryl or 5-10-membered heteroarylhaving 1-5 heteroatoms independently selected from nitrogen, oxygen, orsulfur; and n is 0 to 3.

In other embodiments, for compounds of general formula IA-i-a, IB-i-a,IA-i, or IB-i, ring A is a group selected from:

wherein ring A is optionally further substituted by n occurrences of R²,and wherein R^(2a) is hydrogen or an optionally substituted groupselected from C₁₋₆aliphatic, 3-10-membered cycloaliphatic, 4-10-memberedheterocyclyl having 1-5 heteroatoms independently selected fromnitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-memberedheteroaryl having 1-5 heteroatoms independently selected from nitrogen,oxygen, or sulfur.

In certain other embodiments, for compounds of general formula IA-i-a,IB-i-a, IA-i, or IB-i, Ring A is a group selected from:

wherein ring A is optionally further substituted by n occurrences of R²,and wherein R^(2a) is hydrogen or an optionally substituted groupselected from C₁₋₆aliphatic, 3-10-membered cycloaliphatic, 4-10-memberedheterocyclyl having 1-5 heteroatoms independently selected fromnitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-memberedheteroaryl having 1-5 heteroatoms independently selected from nitrogen,oxygen, or sulfur.

In still other embodiments, ring A is a naphthyl group; each occurrenceof R² is independently halogen, C₁₋₃ alkyl, —CN, C₁₋₃ haloalkyl, —OC₁₋₃alkyl, —OC₁₋₃ haloalkyl, —NHC(O)C₁₋₃ alkyl, —NHC(O)NHC₁₋₃ alkyl,—NHS(O)₂C₁₋₃ alkyl, or —C(O)H; and n is 0 to 3.

In yet other embodiments, ring A is a phenyl group; each occurrence ofR² is independently halogen, C₁₋₃ alkyl, —CN, C₁₋₃ haloalkyl, —OC₁₋₃alkyl, —OC₁₋₃ haloalkyl, —NHC(O)C₁₋₃ alkyl, —NHC(O)NHC₁₋₃ alkyl,—NHS(O)₂C₁₋₃ alkyl, or —C(O)H; and n is 0 to 3.

In still other embodiments, ring A is a naphthyl group, R² is halogenand n is 1 to 2. In yet other embodiments, ring A is a naphthyl groupand n is 0. In yet other embodiments, Ring A is a phenyl group, R² ishalogen and n is 1 to 2.

In certain embodiments, for compounds of general formula IA-i-a, IB-i-a,IA-i, or IB-i, Ring A is 6-10-membered aryl or 5-10-membered heteroarylhaving 1-5 heteroatoms independently selected from nitrogen, oxygen, orsulfur; n is 0 to 3, and W is —C(H)(N(R^(7b))₂)— or —CH₂—, wherein eachoccurrence of R^(7b) is independently hydrogen or optionally substitutedC₁₋₆ aliphatic. In certain embodiments, Ring A is 6-10-membered aryl or5-10-membered heteroaryl having 1-5 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur; n is 0 to 3, and W is —CH₂—.

In certain embodiments, for compounds of general formula IA-i-a, IB-i-a,IA-i, or IB-i, Ring A is a phenyl group; each occurrence of R² isindependently halogen, C₁₋₃ alkyl, —CN, C₁₋₃ haloalkyl, —OC₁₋₃ alkyl,—OC₁₋₃ haloalkyl, —NHC(O)C₁₋₃ alkyl, —NHC(O)NHC₁₋₃ alkyl, —NHS(O)₂C₁₋₃alkyl, or —C(O)H; and n is 0 to 3.

In certain embodiments, for compounds of general formula IA-i-a, IB-i-a,IA-i, or IB-i, Ring A is a phenyl group; each occurrence of R² isindependently halogen, C₁₋₃ alkyl, C₁₋₃ haloalkyl, —OC₁₋₃ alkyl, —OC₁₋₃haloalkyl, —NHC(O)C₁₋₃ alkyl, or -T₂-R^(12d), T₂ is an optionallysubstituted C₁₋₆ alkylene chain, R^(12d) is —N(R^(7b))₂, and eachoccurrence of R^(7b) is independently hydrogen or optionally substitutedC₁₋₆ aliphatic, or any two occurrences of R^(7b) taken together with theatom to which they are bound, form an optionally substituted groupselected from a 3-6-membered cycloaliphatic ring, 6-10-membered aryl,3-6-membered heterocyclyl having 1-5 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur, or 5-10-membered heteroaryl having 1-5heteroatoms independently selected from nitrogen, oxygen, or sulfur; andn is 0 to 3.

In certain embodiments, for compounds of general formula IA-i-a, IB-i-a,IA-i, or IB-i, Ring A is a phenyl group; each occurrence of R² isindependently halogen, —CN, —OC₁₋₃ alkyl, or —OC₁₋₃ haloalkyl; and n is0 to 3. In certain embodiments, Ring A is a phenyl group; eachoccurrence of R² is independently halogen, —CN, —OCH₃, or —OCF₃; and nis 0 to 3.

In still other embodiments, Ring A is a phenyl group, R² is halogen andn is 1 to 2.

In still other embodiments, Ring A is a phenyl group, R² is halogen or(CH₂)N(R^(7b))₂ and each occurrence of R^(7b) is independently hydrogenor optionally substituted C₁₋₆ aliphatic, or any two occurrences ofR^(7b) taken together with the atom to which they are bound, form anoptionally substituted group selected from a 3-6-membered cycloaliphaticring, 6-10-membered aryl, 3-6-membered heterocyclyl having 1-5heteroatoms independently selected from nitrogen, oxygen, or sulfur, or5-10-membered heteroaryl having 1-5 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur; and n is 2.

In certain embodiments, Ring A is a phenyl group, n is 1, and R² is inthe para position. In certain other embodiments, Ring A is a phenylgroup, n is 2, and the two R² groups are in the para and meta positions.In certain other embodiments, Ring A is a phenyl group, n is 2, and thetwo R² groups are in the ortho and meta positions, and para with respectto each other.

In certain embodiments, Ring A is 2-chloro-5(dimethylaminomethyl)phenyl.In certain other embodiments, Ring A is2-chloro-5(pyrrolidin-1-ylmethyl)phenyl.

In certain embodiments, for compounds of general formula IA-i-a, IB-i-a,IA-i, or IB-i, Ring A is a 2-naphthyl group. In certain otherembodiments, Ring A is

In certain embodiments, for compounds of general formula IA-i-a, IB-i-a,IA-i, or IB-i Ring A is a 3-10-membered cycloaliphatic or 4-10-memberedheterocyclyl having 1-5 heteroatoms independently selected fromnitrogen, oxygen, or sulfur. In some embodiments, Ring A is an N-linked3-, 4-, 5-, 6-, or 7-membered heterocyclyl ring. In some embodiments,Ring A is substituted with one or more C₁₋₃ alkyl groups.

In still other embodiments, a compound having the structure of formulaII-i is provided:

wherein Ring A, G₁, W, R², n, m, q, and R¹⁴ are as defined for thecompounds described generally above and in subsets herein.

In certain embodiments, for compounds of general formula II-i:

a) when G₁ is C—CN, HY is unsubstituted morpholine, and W is a covalentbond, then Ring A is other than unsubstituted phenyl, 2-chlorophenyl,4-chlorophenyl, 2-fluorophenyl, 4-fluorophenyl, 2,4-dichlorophenyl,3,4-dichlorophenyl, 4-methylphenyl, 3-methoxyphenyl, 4-methoxyphenyl,3,4-dimethoxyphenyl, 3-(trifluoromethyl)phenyl,4-(trifluoromethyl)phenyl, or 3-(acetylamino)phenyl;b) when G₁ is N, HY is unsubstituted morpholine, and W is a covalentbond, then Ring A is other than unsubstituted phenyl or 2-chlorophenyl;andc) the compound is other than:

In certain embodiments, for compounds of general formula II-i, W is—C(R⁷)₂—, wherein one occurrence of R⁷ is hydrogen and the otheroccurrence of R⁷ is hydrogen, optionally substituted C₁₋₆ aliphatic,—N(R^(7b))₂, or F; and wherein each occurrence of R^(7b) isindependently hydrogen, optionally substituted C₁₋₆ aliphatic,—C(O)R^(7a), or —S(O)₂R^(7a); or wherein two occurrences of R^(7b),taken together with the nitrogen atom to which they are bound, form anoptionally substituted 3-6-membered heterocyclic ring; and eachoccurrence of R^(7a) is independently hydrogen or optionally substitutedC₁₋₆ aliphatic.

In certain embodiments, for compounds of general formula II-i, W is—C(H)(N(R^(7b))₂)— or —CH₂—, wherein each occurrence of R^(7b) isindependently hydrogen or optionally substituted C₁₋₆ aliphatic.

In certain embodiments, for compounds of general formula II-i, W is acovalent bond.

In certain embodiments, for compounds of general formula II-i, Ring A is6-10-membered aryl or 5-10-membered heteroaryl having 1-5 heteroatomsindependently selected from nitrogen, oxygen, or sulfur; and n is 0 to3.

In other embodiments, ring A is a group selected from:

wherein ring A is optionally further substituted by n occurrences of R²,and wherein R^(2a) is hydrogen or an optionally substituted groupselected from C₁₋₆aliphatic, 3-10-membered cycloaliphatic, 4-10-memberedheterocyclyl having 1-5 heteroatoms independently selected fromnitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-memberedheteroaryl having 1-5 heteroatoms independently selected from nitrogen,oxygen, or sulfur.

In certain other embodiments, for compounds of general formula II-i,Ring A is a group selected from:

wherein ring A is optionally further substituted by n occurrences of R²,and wherein R^(2a) is hydrogen or an optionally substituted groupselected from C₁₋₆aliphatic, 3-10-membered cycloaliphatic, 4-10-memberedheterocyclyl having 1-5 heteroatoms independently selected fromnitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-memberedheteroaryl having 1-5 heteroatoms independently selected from nitrogen,oxygen, or sulfur.

In still other embodiments, ring A is a naphthyl group; each occurrenceof R² is independently halogen, C₁₋₃ alkyl, —CN, C₁₋₃ haloalkyl, —OC₁₋₃alkyl, —OC₁₋₃ haloalkyl, —NHC(O)C₁₋₃ alkyl, —NHC(O)NHC₁₋₃ alkyl,—NHS(O)₂C₁₋₃ alkyl, or —C(O)H; and n is 0 to 3.

In still other embodiments, ring A is a naphthyl group, R² is halogenand n is 1 to 2. In yet other embodiments, ring A is a naphthyl groupand n is 0. In yet other embodiments, Ring A is a phenyl group, R² ishalogen and n is 1 to 2.

In certain embodiments, for compounds of general formula II-i, Ring A is6-10-membered aryl or 5-10-membered heteroaryl having 1-5 heteroatomsindependently selected from nitrogen, oxygen, or sulfur; n is 0 to 3,and W is —C(H)(N(R^(7b))₂)— or —CH₂—, wherein each occurrence of R^(7b)is independently hydrogen or optionally substituted C₁₋₆ aliphatic. Incertain embodiments, Ring A is 6-10-membered aryl or 5-10-memberedheteroaryl having 1-5 heteroatoms independently selected from nitrogen,oxygen, or sulfur; n is 0 to 3, and W is —CH₂—.

In certain embodiments, for compounds of general formula II-i, Ring A isa phenyl group; each occurrence of R² is independently halogen, C₁₋₃alkyl, —CN, C₁₋₃ haloalkyl, —OC₁₋₃ alkyl, —OC₁₋₃ haloalkyl, —NHC(O)C₁₋₃alkyl, —NHC(O)NHC₁₋₃ alkyl, —NHS(O)₂C₁₋₃ alkyl, or —C(O)H; and n is 0 to3.

In certain embodiments, for compounds of general formula II-i, Ring A isa phenyl group; each occurrence of R² is independently halogen, C₁₋₃alkyl, C₁₋₃ haloalkyl, —OC₁₋₃ alkyl, —OC₁₋₃ haloalkyl, —NHC(O)C₁₋₃alkyl, or -T₂-R^(12d), T₂ is an optionally substituted C₁₋₆ alkylenechain, R^(12d) is —N(R^(7b))₂, and each occurrence of R^(7b) isindependently hydrogen or optionally substituted C₁₋₆ aliphatic, or anytwo occurrences of R^(7b) taken together with the atom to which they arebound, form an optionally substituted group selected from a 3-6-memberedcycloaliphatic ring, 6-10-membered aryl, 3-6-membered heterocyclylhaving 1-5 heteroatoms independently selected from nitrogen, oxygen, orsulfur, or 5-10-membered heteroaryl having 1-5 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur; and n is 0 to 3.

In certain embodiments, for compounds of general formula II-i, Ring A isa phenyl group; each occurrence of R² is independently halogen, —CN,—OC₁₋₃ alkyl, or —OC₁₋₃ haloalkyl; and n is 0 to 3. In certainembodiments, Ring A is a phenyl group; each occurrence of R² isindependently halogen, —CN, —OCH₃, or —OCF₃; and n is 0 to 3.

In still other embodiments, Ring A is a phenyl group, R² is halogen andn is 1 to 2.

In still other embodiments, Ring A is a phenyl group, R² is halogen or—(CH₂)N(R^(7b))₂ and each occurrence of R^(7b) is independently hydrogenor optionally substituted C₁₋₆ aliphatic, or any two occurrences ofR^(7b) taken together with the atom to which they are bound, form anoptionally substituted group selected from a 3-6-membered cycloaliphaticring, 6-10-membered aryl, 3-6-membered heterocyclyl having 1-5heteroatoms independently selected from nitrogen, oxygen, or sulfur, or5-10-membered heteroaryl having 1-5 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur; and n is 2.

In certain embodiments, Ring A is a phenyl group, n is 1, and R² is inthe para position. In certain other embodiments, Ring A is a phenylgroup, n is 2, and the two R² groups are in the para and meta positions.In certain other embodiments, Ring A is a phenyl group, n is 2, and thetwo R² groups are in the ortho and meta positions, and para with respectto each other.

In certain embodiments, Ring A is 2-chloro-5(dimethylaminomethyl)phenyl.In certain other embodiments, Ring A is2-chloro-5(pyrrolidin-1-ylmethyl)phenyl.

In certain embodiments, for compounds of general formula II-i, Ring A isa 2-naphthyl group. In certain other embodiments, Ring A is

In certain embodiments, for compounds of general formula II-i, Ring A isa 3-10-membered cycloaliphatic or 4-10-membered heterocyclyl having 1-5heteroatoms independently selected from nitrogen, oxygen, or sulfur. Insome embodiments, Ring A is an N-linked 3-, 4-, 5-, 6-, or 7-memberedheterocyclyl ring. In some embodiments, Ring A is substituted with oneor more C₁₋₃ alkyl groups.

In certain embodiments, for compounds of general formula II-i, eachoccurrence of m is 1 and q is 0.

In still other embodiments, a compound having the structure of formulaII-i is provided:

wherein G₁ is N or —CR⁸, and R⁸ is —CN; ring A is a naphthyl group; eachoccurrence of R² is independently halogen, C₁₋₃ alkyl, —CN, C₁₋₃haloalkyl, —OC₁₋₃ alkyl, —OC₁₋₃ haloalkyl, —NHC(O)C₁₋₃ alkyl,—NHC(O)NHC₁₋₃ alkyl, —NHS(O)₂C₁₋₃ alkyl, or —C(O)H; and n is 0 to 3; andW is —C(R⁷)₂—, or >═O, wherein one occurrence of R⁷ is hydrogen and theother occurrence of R⁷ is hydrogen, optionally substituted C₁₋₆aliphatic, —OR^(7a), —N(R^(7b))₂, or F; and wherein each occurrence ofR^(7b) is independently hydrogen, optionally substituted C₁₋₆ aliphatic,—C(O)R^(7a), or —S(O)₂R^(7a); or wherein two occurrences of R^(7b),taken together with the nitrogen atom to which they are bound, form anoptionally substituted 3-6-membered heterocyclic ring; and eachoccurrence of R^(7a) is independently hydrogen or optionally substitutedC₁₋₆ aliphatic.

In still other embodiments, a compound having the structure of formulaIII-i is provided:

wherein G₁ is N or —CR⁸, and R⁸ is —CN; and wherein Ring A, n and R² areas defined for the compounds described generally and in subsets herein.

In certain embodiments, for compounds of general formula III-i, Ring Ais 6-10-membered aryl or 5-10-membered heteroaryl having 1-5 heteroatomsindependently selected from nitrogen, oxygen, or sulfur; and n is 0 to3.

In other embodiments, ring A is a group selected from:

wherein ring A is optionally further substituted by n occurrences of R²,and wherein R^(2a) is hydrogen or an optionally substituted groupselected from C₁₋₆aliphatic, 3-10-membered cycloaliphatic, 4-10-memberedheterocyclyl having 1-5 heteroatoms independently selected fromnitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-memberedheteroaryl having 1-5 heteroatoms independently selected from nitrogen,oxygen, or sulfur.

In certain other embodiments, for compounds of general formula III-i,Ring A is a group selected from:

wherein ring A is optionally further substituted by n occurrences of R²,and wherein R² is hydrogen or an optionally substituted group selectedfrom C₁₋₆aliphatic, 3-10-membered cycloaliphatic, 4-10-memberedheterocyclyl having 1-5 heteroatoms independently selected fromnitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-memberedheteroaryl having 1-5 heteroatoms independently selected from nitrogen,oxygen, or sulfur.

In still other embodiments, ring A is a naphthyl group; each occurrenceof R² is independently halogen, C₁₋₃ alkyl, —CN, C₁₋₃ haloalkyl, —OC₁₋₃alkyl, —OC₁₋₃ haloalkyl, —NHC(O)C₁₋₃ alkyl, —NHC(O)NHC₁₋₃ alkyl,—NHS(O)₂C₁₋₃ alkyl, or —C(O)H; and n is 0 to 3.

In still other embodiments, ring A is a naphthyl group, R² is halogenand n is 1 to 2. In yet other embodiments, ring A is a naphthyl groupand n is 0. In yet other embodiments, Ring A is a phenyl group, R² ishalogen and n is 1 to 2.

In certain embodiments, for compounds of general formula III-i, Ring Ais a phenyl group; each occurrence of R² is independently halogen, C₁₋₃alkyl, —CN, C₁₋₃ haloalkyl, —OC₁₋₃ alkyl, —OC₁₋₃ haloalkyl, —NHC(O)C₁₋₃alkyl, —NHC(O)NHC₁₋₃ alkyl, —NHS(O)₂C₁₋₃ alkyl, or —C(O)H; and n is 0 to3.

In certain embodiments, for compounds of general formula III-i, Ring Ais a phenyl group; each occurrence of R² is independently halogen, C₁₋₃alkyl, C₁₋₃ haloalkyl, —OC₁₋₃ alkyl, —OC₁₋₃ haloalkyl, —NHC(O)C₁₋₃alkyl, or -T₂-R^(12d), T₂ is an optionally substituted C₁₋₆ alkylenechain, R^(12d) is —N(R^(7b))₂, and each occurrence of R^(7b) isindependently hydrogen or optionally substituted C₁₋₆ aliphatic, or anytwo occurrences of R^(7b) taken together with the atom to which they arebound, form an optionally substituted group selected from a 3-6-memberedcycloaliphatic ring, 6-10-membered aryl, 3-6-membered heterocyclylhaving 1-5 heteroatoms independently selected from nitrogen, oxygen, orsulfur, or 5-10-membered heteroaryl having 1-5 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur; and n is 0 to 3.

In certain embodiments, for compounds of general formula III-i, Ring Ais a phenyl group; each occurrence of R² is independently halogen, —CN,—OC₁₋₃ alkyl, or —OC₁₋₃ haloalkyl; and n is 0 to 3. In certainembodiments, Ring A is a phenyl group; each occurrence of R² isindependently halogen, —CN, —OCH₃, or —OCF₃; and n is 0 to 3.

In still other embodiments, Ring A is a phenyl group, R² is halogen andn is 1 to 2.

In still other embodiments, Ring A is a phenyl group, R² is halogen or(CH₂)N(R^(7b))₂ and each occurrence of R^(7b) is independently hydrogenor optionally substituted C₁₋₆ aliphatic, or any two occurrences ofR^(7b) taken together with the atom to which they are bound, form anoptionally substituted group selected from a 3-6-membered cycloaliphaticring, 6-10-membered aryl, 3-6-membered heterocyclyl having 1-5heteroatoms independently selected from nitrogen, oxygen, or sulfur, or5-10-membered heteroaryl having 1-5 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur; and n is 2.

In certain embodiments, Ring A is a phenyl group, n is 1, and R² is inthe para position. In certain other embodiments, Ring A is a phenylgroup, n is 2, and the two R² groups are in the para and meta positions.In certain other embodiments, Ring A is a phenyl group, n is 2, and thetwo R² groups are in the ortho and meta positions, and para with respectto each other.

In certain embodiments, Ring A is 2-chloro-5(dimethylaminomethyl)phenyl.In certain other embodiments, Ring A is2-chloro-5(pyrrolidin-1-ylmethyl)phenyl.

In certain embodiments, for compounds of general formula III-i, Ring Ais a 2-naphthyl group. In certain other embodiments, Ring A is

In certain embodiments, for compounds of general formula III-i, Ring Ais a 3-10-membered cycloaliphatic or 4-10-membered heterocyclyl having1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur.In some embodiments, Ring A is an N-linked 3-, 4-, 5-, 6-, or 7-memberedheterocyclyl ring. In some embodiments, Ring A is substituted with oneor more C₁₋₃ alkyl groups.

In yet other embodiments, a compound having the structure of formulaIV-i is provided:

wherein Ring A, G₁, n and R² are as defined for compounds describedgenerally above in subsets herein.

In certain embodiments, for compounds of general formula IV-i:

a) when G₁ is C—CN, then Ring A is other than unsubstituted phenyl,2-chlorophenyl, 4-chlorophenyl, 2-fluorophenyl, 4-fluorophenyl,2,4-dichlorophenyl, 3,4-dichlorophenyl, 4-methylphenyl, 3-methoxyphenyl,4-methoxyphenyl, 3,4-dimethoxyphenyl, 3-(trifluoromethyl)phenyl,4-(trifluoromethyl)phenyl, or 3-(acetylamino)phenyl;b) when G₁ is N, then Ring A is other than unsubstituted phenyl or2-chlorophenyl; andc) the compound is other than:

In certain embodiments, for compounds of general formula IV-i, Ring A is6-10-membered aryl or 5-10-membered heteroaryl having 1-5 heteroatomsindependently selected from nitrogen, oxygen, or sulfur; and n is 0 to3.

In other embodiments, ring A is a group selected from:

wherein ring A is optionally further substituted by n occurrences of R²,and wherein R² is hydrogen or an optionally substituted group selectedfrom C₁₋₆aliphatic, 3-10-membered cycloaliphatic, 4-10-memberedheterocyclyl having 1-5 heteroatoms independently selected fromnitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-memberedheteroaryl having 1-5 heteroatoms independently selected from nitrogen,oxygen, or sulfur.

In certain other embodiments, for compounds of general formula VI-i,Ring A is a group selected from:

wherein ring A is optionally further substituted by n occurrences of R²,and wherein R^(2a) is hydrogen or an optionally substituted groupselected from C₁₋₆aliphatic, 3-10-membered cycloaliphatic, 4-10-memberedheterocyclyl having 1-5 heteroatoms independently selected fromnitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-memberedheteroaryl having 1-5 heteroatoms independently selected from nitrogen,oxygen, or sulfur.

In still other embodiments, ring A is a naphthyl group; each occurrenceof R² is independently halogen, C₁₋₃ alkyl, —CN, C₁₋₃ haloalkyl, —OC₁₋₃alkyl, —OC₁₋₃ haloalkyl, —NHC(O)C₁₋₃ alkyl, —NHC(O)NHC₁₋₃ alkyl,—NHS(O)₂C₁₋₃ alkyl, or —C(O)H; and n is 0 to 3.

In still other embodiments, ring A is a naphthyl group, R² is halogenand n is 1 to 2. In yet other embodiments, ring A is a naphthyl groupand n is 0. In yet other embodiments, Ring A is a phenyl group, R² ishalogen and n is 1 to 2.

In certain embodiments, for compounds of general formula IV-i, Ring A isa phenyl group; each occurrence of R² is independently halogen, C₁₋₃alkyl, —CN, C₁₋₃ haloalkyl, —OC₁₋₃ alkyl, —OC₁₋₃ haloalkyl, —NHC(O)C₁₋₃alkyl, —NHC(O)NHC₁₋₃ alkyl, —NHS(O)₂C₁₋₃ alkyl, or —C(O)H; and n is 0 to3.

In certain embodiments, for compounds of general formula IV-i, Ring A isa phenyl group; each occurrence of R² is independently halogen, C₁₋₃alkyl, C₁₋₃ haloalkyl, —OC₁₋₃ alkyl, —OC₁₋₃ haloalkyl, —NHC(O)C₁₋₃alkyl, or -T₂-R^(12d), T₂ is an optionally substituted C₁₋₆ alkylenechain, R^(12d) is —N(R^(7b))₂, and each occurrence of R^(7b) isindependently hydrogen or optionally substituted C₁₋₆ aliphatic, or anytwo occurrences of R^(7b) taken together with the atom to which they arebound, form an optionally substituted group selected from a 3-6-memberedcycloaliphatic ring, 6-10-membered aryl, 3-6-membered heterocyclylhaving 1-5 heteroatoms independently selected from nitrogen, oxygen, orsulfur, or 5-10-membered heteroaryl having 1-5 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur; and n is 0 to 3.

In certain embodiments, for compounds of general formula IV-i, Ring A isa phenyl group; each occurrence of R² is independently halogen, —CN,—OC₁₋₃ alkyl, or —OC₁₋₃ haloalkyl; and n is 0 to 3. In certainembodiments, Ring A is a phenyl group; each occurrence of R² isindependently halogen, —CN, —OCH₃, or —OCF₃; and n is 0 to 3.

In still other embodiments, Ring A is a phenyl group, R² is halogen andn is 1 to 2.

In still other embodiments, Ring A is a phenyl group, R² is halogen or—(CH₂)N(R^(7b))₂ and each occurrence of R^(7b) is independently hydrogenor optionally substituted C₁₋₆ aliphatic, or any two occurrences ofR^(7b) taken together with the atom to which they are bound, form anoptionally substituted group selected from a 3-6-membered cycloaliphaticring, 6-10-membered aryl, 3-6-membered heterocyclyl having 1-5heteroatoms independently selected from nitrogen, oxygen, or sulfur, or5-10-membered heteroaryl having 1-5 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur; and n is 2.

In certain embodiments, Ring A is a phenyl group, n is 1, and R² is inthe para position. In certain other embodiments, Ring A is a phenylgroup, n is 2, and the two R² groups are in the para and meta positions.In certain other embodiments, Ring A is a phenyl group, n is 2, and thetwo R² groups are in the ortho and meta positions, and para with respectto each other.

In certain embodiments, Ring A is 2-chloro-5(dimethylaminomethyl)phenyl.In certain other embodiments, Ring A is2-chloro-5(pyrrolidin-1-ylmethyl)phenyl.

In certain embodiments, for compounds of general formula IV-i, Ring A isa 2-naphthyl group. In certain other embodiments, Ring A is

In certain embodiments, for compounds of general formula IV-i, Ring A isa 3-10-membered cycloaliphatic or 4-10-membered heterocyclyl having 1-5heteroatoms independently selected from nitrogen, oxygen, or sulfur. Insome embodiments, Ring A is an N-linked 3-, 4-, 5-, 6-, or 7-memberedheterocyclyl ring. In some embodiments, Ring A is substituted with oneor more C₁₋₃ alkyl groups.

In certain embodiments, for compounds of general formula IA-i or IB-i,HY is selected from:

wherein each HY group is optionally additionally substituted with one ormore occurrences of R¹⁴.

In yet other embodiments, for compounds of general formula IA-i or IB-i,G₁ is N.

4. Uses, Formulation and Administration

As discussed above, the present invention provides compounds that areuseful as inhibitors of PI3K enzymes, and thus the present compounds areuseful for treating proliferative, inflammatory, or cardiovasculardisorders such as tumor and/or cancerous cell growth mediated by PI3K.In particular, the compounds are useful in the treatment of cancers in asubject, including, but not limited to, lung and bronchus, prostate,breast, pancreas, colon and recum, thyroid, liver and intrahepatic bileduct, hepatocellular, gastric, gliomaglioblastoma, endometrial,melanoma, kidney, and renal pelvis, urinary bladder, utering corpus,uterine cervix, ovary, multiple myeloma, esophagus, acute myelogenousleukemia, chronic myelogenous leukemia, lymphocytic leukemia, myeloidleukemia, brain, oral cavity, and pharynx, small intestine, non-Hodgkinlymphoma, and villous colon adenoma.

In some embodiments, compounds of the invention are suitable for thetreatment of breast cancer, bladder cancer, colon cancer, glioma,glioblastoma, lung cancer, hepatocellular cancer, gastric cancer,melanoma, thyroid cancer, endometrial cancer, renal cancer, cervicalcancer, pancreatic cancer, esophageal cancer, prostate cancer, braincancer, or ovarian cancer.

In other embodiments, compounds of the invention are suitable for thetreatment of inflammatory and cardiovascular disorders including, butnot limited to, allergies/anaphylaxis, acute and chronic inflammation,rheumatoid arthritis; autoimmunity disorders, thrombosis, hypertension,cardiac hypertrophy, and heart failure.

Accordingly, in another aspect of the present invention, pharmaceuticalcompositions are provided, wherein these compositions comprise any ofthe compounds as described herein, and optionally comprise apharmaceutically acceptable carrier, adjuvant or vehicle. In certainembodiments, these compositions optionally further comprise one or moreadditional therapeutic agents.

It will also be appreciated that certain of the compounds of presentinvention can exist in free form for treatment, or where appropriate, asa pharmaceutically acceptable derivative thereof. According to thepresent invention, a pharmaceutically acceptable derivative includes,but is not limited to, pharmaceutically acceptable prodrugs, salts,esters, salts of such esters, or any other adduct or derivative whichupon administration to a patient in need is capable of providing,directly or indirectly, a compound as otherwise described herein, or ametabolite or residue thereof.

As used herein, the term “pharmaceutically acceptable salt” refers tothose salts which are, within the scope of sound medical judgment,suitable for use in contact with the tissues of humans and lower animalswithout undue toxicity, irritation, allergic response and the like, andare commensurate with a reasonable benefit/risk ratio. A“pharmaceutically acceptable salt” means any non-toxic salt or salt ofan ester of a compound of this invention that, upon administration to arecipient, is capable of providing, either directly or indirectly, acompound of this invention or an inhibitorily active metabolite orresidue thereof. As used herein, the term “inhibitorily activemetabolite or residue thereof” means that a metabolite or residuethereof is also an inhibitor of PI3K.

Pharmaceutically acceptable salts are well known in the art. Forexample, S. M. Berge et al., describe pharmaceutically acceptable saltsin detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporatedherein by reference. Pharmaceutically acceptable salts of the compoundsof this invention include those derived from suitable inorganic andorganic acids and bases. Examples of pharmaceutically acceptable,nontoxic acid addition salts are salts of an amino group formed withinorganic acids such as hydrochloric acid, hydrobromic acid, phosphoricacid, sulfuric acid and perchloric acid or with organic acids such asacetic acid, oxalic acid, maleic acid, tartaric acid, citric acid,succinic acid or malonic acid or by using other methods used in the artsuch as ion exchange. Other pharmaceutically acceptable salts includeadipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate,bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate,cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate,formate, fumarate, glucoheptonate, glycerophosphate, gluconate,hemisulfate, heptanoate, hexanoate, hydroiodide,2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, laurylsulfate, malate, maleate, malonate, methanesulfonate,2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate,pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate,pivalate, propionate, stearate, succinate, sulfate, tartrate,thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and thelike. Salts derived from appropriate bases include alkali metal,alkaline earth metal, ammonium and N⁺(C₁₋₄alkyl)₄ salts. This inventionalso envisions the quaternization of any basic nitrogen-containinggroups of the compounds disclosed herein. Water or oil-soluble ordispersable products may be obtained by such quaternization.Representative alkali or alkaline earth metal salts include sodium,lithium, potassium, calcium, magnesium, and the like. Furtherpharmaceutically acceptable salts include, when appropriate, nontoxicammonium, quaternary ammonium, and amine cations formed usingcounterions such as halide, hydroxide, carboxylate, sulfate, phosphate,nitrate, loweralkyl sulfonate and aryl sulfonate.

As described above, the pharmaceutically acceptable compositions of thepresent invention additionally comprise a pharmaceutically acceptablecarrier, adjuvant, or vehicle, which, as used herein, includes any andall solvents, diluents, or other liquid vehicle, dispersion orsuspension aids, surface active agents, isotonic agents, thickening oremulsifying agents, preservatives, solid binders, lubricants and thelike, as suited to the particular dosage form desired. Remington'sPharmaceutical Sciences, Sixteenth Edition, E. W. Martin (MackPublishing Co., Easton, Pa., 1980) discloses various carriers used informulating pharmaceutically acceptable compositions and knowntechniques for the preparation thereof. Except insofar as anyconventional carrier medium is incompatible with the compounds of theinvention, such as by producing any undesirable biological effect orotherwise interacting in a deleterious manner with any othercomponent(s) of the pharmaceutically acceptable composition, its use iscontemplated to be within the scope of this invention. Some examples ofmaterials which can serve as pharmaceutically acceptable carriersinclude, but are not limited to, ion exchangers, alumina, aluminumstearate, lecithin, serum proteins, such as human serum albumin, buffersubstances such as phosphates, glycine, sorbic acid, or potassiumsorbate, partial glyceride mixtures of saturated vegetable fatty acids,water, salts or electrolytes, such as protamine sulfate, disodiumhydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zincsalts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone,polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, woolfat, sugars such as lactose, glucose and sucrose; starches such as cornstarch and potato starch; cellulose and its derivatives such as sodiumcarboxymethyl cellulose, ethyl cellulose and cellulose acetate; powderedtragacanth; malt; gelatin; talc; excipients such as cocoa butter andsuppository waxes; oils such as peanut oil, cottonseed oil; saffloweroil; sesame oil; olive oil; corn oil and soybean oil; glycols; such apropylene glycol or polyethylene glycol; esters such as ethyl oleate andethyl laurate; agar; buffering agents such as magnesium hydroxide andaluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline;Ringer's solution; ethyl alcohol, and phosphate buffer solutions, aswell as other non-toxic compatible lubricants such as sodium laurylsulfate and magnesium stearate, as well as coloring agents, releasingagents, coating agents, sweetening, flavoring and perfuming agents,preservatives and antioxidants can also be present in the composition,according to the judgment of the formulator.

In yet another aspect, a method for treating a proliferative,inflammatory, or cardiovascular disorder is provided comprisingadministering an effective amount of a compound, or a pharmaceuticalcomposition to a subject in need thereof. In certain embodiments of thepresent invention an “effective amount” of the compound orpharmaceutical composition is that amount effective for treating aproliferative, inflammatory, or cardiovascular disorder, or is thatamount effective for treating cancer. In other embodiments, an“effective amount” of a compound is an amount which inhibits binding ofPI3K and thereby blocks the resulting signaling cascades that lead tothe abnormal activity of growth factors, receptor tyrosine kinases,protein serine/threonine kinases, G protein coupled receptors andphospholipid kinases and phosphatases.

The compounds and compositions, according to the method of the presentinvention, may be administered using any amount and any route ofadministration effective for treating the disease. The exact amountrequired will vary from subject to subject, depending on the species,age, and general condition of the subject, the severity of theinfection, the particular agent, its mode of administration, and thelike. The compounds of the invention are preferably formulated in dosageunit form for ease of administration and uniformity of dosage. Theexpression “dosage unit form” as used herein refers to a physicallydiscrete unit of agent appropriate for the patient to be treated. Itwill be understood, however, that the total daily usage of the compoundsand compositions of the present invention will be decided by theattending physician within the scope of sound medical judgment. Thespecific effective dose level for any particular patient or organismwill depend upon a variety of factors including the disease beingtreated and the severity of the disease; the activity of the specificcompound employed; the specific composition employed; the age, bodyweight, general health, sex and diet of the patient; the time ofadministration, route of administration, and rate of excretion of thespecific compound employed; the duration of the treatment; drugs used incombination or coincidental with the specific compound employed, andlike factors well known in the medical arts. The term “patient”, as usedherein, means an animal, preferably a mammal, and most preferably ahuman.

The pharmaceutically acceptable compositions of this invention can beadministered to humans and other animals orally, rectally, parenterally,intracisternally, intravaginally, intraperitoneally, topically (as bypowders, ointments, or drops), bucally, as an oral or nasal spray, orthe like, depending on the severity of the infection being treated. Incertain embodiments, the compounds of the invention may be administeredorally or parenterally at dosage levels of about 0.01 mg/kg to about 50mg/kg and preferably from about 1 mg/kg to about 25 mg/kg, of subjectbody weight per day, one or more times a day, to obtain the desiredtherapeutic effect.

Liquid dosage forms for oral administration include, but are not limitedto, pharmaceutically acceptable emulsions, microemulsions, solutions,suspensions, syrups and elixirs. In addition to the active compounds,the liquid dosage forms may contain inert diluents commonly used in theart such as, for example, water or other solvents, solubilizing agentsand emulsifiers such as ethyl alcohol, isopropyl alcohol, ethylcarbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butylene glycol, dimethylformamide, oils (in particular,cottonseed, groundnut, corn, germ, olive, castor, and sesame oils),glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fattyacid esters of sorbitan, and mixtures thereof. Besides inert diluents,the oral compositions can also include adjuvants such as wetting agents,emulsifying and suspending agents, sweetening, flavoring, and perfumingagents.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectablesolution, suspension or emulsion in a nontoxic parenterally acceptablediluent or solvent, for example, as a solution in 1,3-butanediol. Amongthe acceptable vehicles and solvents that may be employed are water,Ringer's solution, U.S.P. and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose any bland fixed oil can beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid are used in the preparation of injectables.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter, or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium prior to use.

In order to prolong the effect of a compound of the present invention,it is often desirable to slow the absorption of the compound fromsubcutaneous or intramuscular injection. This may be accomplished by theuse of a liquid suspension of crystalline or amorphous material withpoor water solubility. The rate of absorption of the compound thendepends upon its rate of dissolution that, in turn, may depend uponcrystal size and crystalline form. Alternatively, delayed absorption ofa parenterally administered compound form is accomplished by dissolvingor suspending the compound in an oil vehicle. Injectable depot forms aremade by forming microencapsule matrices of the compound in biodegradablepolymers such as polylactide-polyglycolide. Depending upon the ratio ofcompound to polymer and the nature of the particular polymer employed,the rate of compound release can be controlled. Examples of otherbiodegradable polymers include poly(orthoesters) and poly(anhydrides).Depot injectable formulations are also prepared by entrapping thecompound in liposomes or microemulsions that are compatible with bodytissues.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable non-irritating excipients or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat ambient temperature but liquid at body temperature and therefore meltin the rectum or vaginal cavity and release the active compound.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activecompound is mixed with at least one inert, pharmaceutically acceptableexcipient or carrier such as sodium citrate or dicalcium phosphateand/or a) fillers or extenders such as starches, lactose, sucrose,glucose, mannitol, and silicic acid, b) binders such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone,sucrose, and acacia, c) humectants such as glycerol, d) disintegratingagents such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate, e) solutionretarding agents such as paraffin, f) absorption accelerators such asquaternary ammonium compounds, g) wetting agents such as, for example,cetyl alcohol and glycerol monostearate, h) absorbents such as kaolinand bentonite clay, and i) lubricants such as talc, calcium stearate,magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate,and mixtures thereof. In the case of capsules, tablets and pills, thedosage form may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such excipients as lactoseor milk sugar as well as high molecular weight polyethylene glycols andthe like. The solid dosage forms of tablets, dragees, capsules, pills,and granules can be prepared with coatings and shells such as entericcoatings and other coatings well known in the pharmaceutical formulatingart. They may optionally contain opacifying agents and can also be of acomposition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions that can be usedinclude polymeric substances and waxes. Solid compositions of a similartype may also be employed as fillers in soft and hard-filled gelatincapsules using such excipients as lactose or milk sugar as well as highmolecular weight polethylene glycols and the like.

The active compounds can also be in micro-encapsulated form with one ormore excipients as noted above. The solid dosage forms of tablets,dragees, capsules, pills, and granules can be prepared with coatings andshells such as enteric coatings, release controlling coatings and othercoatings well known in the pharmaceutical formulating art. In such soliddosage forms the active compound may be admixed with at least one inertdiluent such as sucrose, lactose or starch. Such dosage forms may alsocomprise, as is normal practice, additional substances other than inertdiluents, e.g., tableting lubricants and other tableting aids such amagnesium stearate and microcrystalline cellulose. In the case ofcapsules, tablets and pills, the dosage forms may also comprisebuffering agents. They may optionally contain opacifying agents and canalso be of a composition that they release the active ingredient(s)only, or preferentially, in a certain part of the intestinal tract,optionally, in a delayed manner. Examples of embedding compositions thatcan be used include polymeric substances and waxes.

Dosage forms for topical or transdermal administration of a compound ofthis invention include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants or patches. The active componentis admixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives or buffers as may be required.Ophthalmic formulation, ear drops, and eye drops are also contemplatedas being within the scope of this invention. Additionally, the presentinvention contemplates the use of transdermal patches, which have theadded advantage of providing controlled delivery of a compound to thebody. Such dosage forms can be made by dissolving or dispensing thecompound in the proper medium. Absorption enhancers can also be used toincrease the flux of the compound across the skin. The rate can becontrolled by either providing a rate controlling membrane or bydispersing the compound in a polymer matrix or gel.

While one or more of the inventive compounds may be used in anapplication of monotherapy to treat a disorder, disease or symptom, theyalso may be used in combination therapy, in which the use of aninventive compound or composition (therapeutic agent) is combined withthe use of one or more other therapeutic agents for treating the sameand/or other types of disorders, symptoms and diseases. Combinationtherapy includes administration of the therapeutic agents concurrentlyor sequentially. Alternatively, the therapeutic agents can be combinedinto one composition which is administered to the patient.

In one embodiment, the compounds of this invention are used incombination with other therapeutic agents, such as other inhibitors ofPI3K or other inhibitors such as mTor. In some embodiments, a compoundof the invention is administered in conjunction with a therapeutic agentselected from the group consisting of cytotoxic agents, radiotherapy,and immunotherapy. It is understood that other combinations may beundertaken while remaining within the scope of the invention.

Another aspect of the invention relates to inhibiting PI3K, activity ina biological sample or a patient, which method comprises administeringto the patient, or contacting said biological sample with a compound offormula I or a composition comprising said compound. The term“biological sample”, as used herein, generally includes in vivo, invitro, and ex vivo materials, and also includes, without limitation,cell cultures or extracts thereof; biopsied material obtained from amammal or extracts thereof; and blood, saliva, urine, feces, semen,tears, or other body fluids or extracts thereof.

Still another aspect of this invention is to provide a kit comprisingseparate containers in a single package, wherein the inventivepharmaceutical compounds, compositions and/or salts thereof are used incombination with pharmaceutically acceptable carriers to treatdisorders, symptoms and diseases where PI3K kinase plays a role.

EXPERIMENTAL PROCEDURES I-A. Preparation of Certain Exemplary Compounds

Compounds 1 through 92 (Shown in Table 1 below) were prepared using thegeneral methods and specific examples described directly below.

1. General Synthetic Methods and Intermediates

The compounds of the present invention can be prepared by methods knownto one of ordinary skill in the art and or by reference to the schemesshown below and the synthetic examples that follow. Exemplary syntheticroutes are set forth in Schemes 1-52 below, and in the Examples.

In methods defined below X represents halogen (Br, I or Cl), P is HYitself or a substituent convertible to HY by applying a generally knownmethod, R^(A) represents Ring A, W^(R) is W—R^(A) itself, or asubstituent convertible to W—R^(A) by applying a generally known method,W^(L) is R^(A) itself, or a part of W linker connected to R^(A) and Q isR¹ itself or a substituent convertible to R¹ by applying a generallyknown method.

Examples of the solvent for the below-mentioned reactions include, butare not limited to halogenated hydrocarbons such as dichloromethane,chloroform, carbon tetrachloride, 1,2-dichloroethane and the like,aromatic hydrocarbons such as benzene, toluene, xylene and the like,alcohols such as methanol, ethanol, isopropanol, tert-butanol, phenoland the like, ethers such as diethyl ether, tetrahydrofuran, dioxane,DME and the like, acetone, acetonitrile, ethyl acetate,N,N-dimethylformamide, N,N-dimethylacetamide, 1-methyl-2-pyrrolidone,dimethyl sulfoxide, hexamethylphosphoramide, water or a mixed solventthereof and the like.

One of ordinary skill in the art will recognise that numerous variationsin reaction conditions including variations in solvent, reagents,catalysts, reaction temperatures and times are possible for each of thereactions described. Variation of order of synthetic steps andalternative synthetic routes are also possible.

In many cases, synthesis can be started from commercially availablethiophene thiazole analogs to prepare target compounds. In some cases,specially functionalized thiophene thiazole analogs can be prepared bythe procedures described in Schemes 1-4.

Scheme 1 shows a procedure to prepare compounds of formula v.

Condensation of nitriles i with 2,5-dihydroxy-1,4-dithiane can beaccomplished using reported procedure (C. E. Stephens et al. Bioorg.Med. Chem., 2001, 9, 1123-1132, Method A). Aminothiophenes ii may thenbe protected with an appropriate protecting group, for example Boc usingstandard conditions, such as Boc anhydride, DMAP, dioxane (Method B).Halogenation of protected thiophenes iii may be achieved using asuitable reagent, for example NBS in DCM to afford halides of formula iv(Method C), that can be converted into compounds of formula v by acombination of generally known functional group conversion reactionsdescribed below.

Alternatively, reverse type of thiophene analogs vi can also be preparedusing functional group transformations described below.

Suitably functionalized 4-hydroxyl thiophenes can be prepared accordingto the published procedure such as M. D. Mullican, et al., J. Med.Chem., 1991, 34, 2186-2194.

For example, scheme 2 describes a general procedure for preparing4-hydroxy thiophenes of formula x. Beta-ketoesters vii may be treatedwith thiols, such as methyl thioglycolate viii in the presence ofsuitable acid, such as HCl in ethanol (Method D), to afford dithio-ketalix, which may then be treated with an appropriate base, like sodiumethoxide in a suitable solvent, for example, ethanol, to give 4-hydroxythiophenes of formula x (Method E). These 4-hydroxy thiophenes can beconverted to target compounds v according to the procedures describedbelow.

Scheme 3 shows a general route for the synthesis of compounds of formulaxiii and xvi. Thioamides xi or thioureas (When P═NHR) may be treatedwith alpha-halogenated carbonyl compounds xii in a suitable solvent,such as isopropanol at elevated temperature to give thiazoles xiii.(Method F). When P═NH₂, 2-aminothiazoles xiii that are obtained can bethen subjected to Sandmeyer reaction to afford 2-halothiazoles xxxi(P═X), which can be used for further functional transformationsdescribed below. A conversion reaction from xiii to compounds xiv can beperformed, for example, by a combination of generally known functionalgroup conversion reactions shown below.

If an alpha-halogenated carbonyl compound is suitably selected, i.e. xv,reverse type thiazole analogs xvi and xvii can be also prepared usingwell known organic functional group transformation reactions describedbelow.

As shown in scheme 4, thioamides xi can be condensed withalpha-halogenated esters in a similar manner as reported by Rzasa, R. M.et al, Bioorg. Med. Chem. 2007, 15, 6574 to obtain 4-hydroxythiazolederivatives xviii. The reaction can be carried out in a suitablesolvent, such as ethanol, in the presence of an appropriate base, i.e.,pyridine, under elevated temperature (Method G).

Schemes 5-19 describe procedures for basic functional grouptransformations on thiophene thiazole central core scaffolds.

In the schemes 5-8, general functional group transformation proceduresfor introduction of the HY group are described.

Scheme 5 describes the procedure for the introduction of HY to3-cyanothiophene analogs by a known functional group transformationreaction.

As shown in Scheme 5, sulfones of formula xix (synthetic examples givenin Mansanet et al, WO 2005070916) may be treated with amines R′—NH₂,such as 2,4-dimethoxybenzylamine, in a suitable solvent, e.g., THF, atelevated temperature (Method H) to give xx.Deprotection of R″ group may be carried out using a standard procedure,in the case of dimethoxybenzyl group with an acid, such as TFA in DCM,to afford amines xxi (Method I).Amines xxi can then be subjected to Sandmeyer reaction using appropriatereagents, such as methylene iodide and amyl nitrite in ACN (Method J).The resulting halogenated thiophenes xxii can be coupled with arylstannanes under suitable conditions, for example Pd(PPh₃)₄, CuI, LiCl ina suitable solvent, such as dioxane, at elevated temperature to givecompounds of formula xxiii (Method K). Alternatively, boronic acids oresters can be used for such coupling reactions, for example Pd(PPh₃)₄,Na₂CO₃, DME/water, elevated temperature or microwave irradiation (MethodL).A conversion reaction from xxiii to compounds xxiv can be performed, forexample, by a combination of generally known functional group conversionreactions shown below.

Scheme 6 shows a general route for introducing HY to unsubstituted2-position of thiophene core.

2-unsubstituted thiophenes xxv can be treated with suitable base, suchas n-BuLi in THF at low temperature, to produce lithiated thiopheneintermediates xxvi (Method M). The intermediate organolithium speciescan be quenched with halogen molecule, for example iodine in a suitablesolvent, such as THF, to afford halogenated compounds of formula xxvii(Method N). Alternatively, thiophenes xxv can be directly halogenatedusing suitable conditions, for example NBS in DCM to afford halogenatedcompounds of formula xxvii (Method C). Halides xxvii can be coupled witharyl stannanes under suitable conditions, for example Pd(PPh₃)₄, CuI,LiCl in a suitable solvent, such as dioxane at elevated temperature togive compounds of formula xxviii (Method K), or boronic acids or esters.with an appropriate catalyst, for example Pd(PPh₃)₄, in the presence ofa suitable base, such as sodium carbonate, in DME-water mixture atelevated temperature (Method L) to afford compounds of formula xxviii.Alternatively, lithium intermediates xxvi can be transformed toorganometallic reagents, such as stannanes by quenching with suitabletin halide, such as tributyltin chloride (Method O), or boronic esters,such as alkoxy-tetramethyl-1,3,2-dioxaborolane (method DA), ortrifluoroborates by the subsequent treatment of boronic esters with asuitable fluorine source, such as KHF₂ (Method DB). Stannanes xxix maythen be coupled with aryl halides, triflates, or mesylates usingappropriate conditions, such as Pd(PPh₃)₄, CuI, LiCl in a suitablesolvent, such as dioxane, at elevated temperature to give compounds offormula xxviii (Method K). Boronic acids, esters or trifluoroborates canbe then coupled with aryl halides, triflates, or mesylates with anappropriate catalyst, for example Pd(PPh₃)₄, in the presence of asuitable base, such as sodium carbonate in DME-water mixture at elevatedtemperature (Method L) to afford compounds of formula xxviii.A conversion reaction from xxviii to compounds v can be performed, forexample, by a combination of generally known functional group conversionreactions shown below.

Scheme 7 shows a general route for introducing HY to 2-position ofthiazole core scaffold. Halogenated thiazoles xxxi, which may beavailable as described in scheme 3, can coupled with suitable partners,such as boronic acids, stannanes, etc under standard Suzuki conditions,such as Pd(PPh₃)₄, Na₂CO₃, DME/water, elevated temperature or microwaveirradiation (Method L), or standard Stille conditions, such asPd(PPh₃)₄, CuI, LiCl, dioxane at elevated temperature (Method K) toafford compounds of formula xiii.

A conversion reaction from xiii to compounds xiv can be performed, forexample, by a combination of generally known functional group conversionreactions shown below.

Scheme 8 describes the procedure for the synthesis of 3-cyanothiophenesxxxiv. Substituted alkoxyethenamine xxx may be treated withmalononitrile in the presence of a suitable base, such as TEA, in asuitable solvent, like chloroform, at elevated temperature to affordsubstituted aminoethylene malononitriles xxxii (Method P), that aretreated with sulfur under suitable conditions, such as DMF and elevatedtemperature, to give diaminocyanothiophenes xxxiii (Method Q). Diaminesxxxiii may then be subjected to a Sandmeyer reaction using appropriatereagents, such as copper(II)bromide, amyl nitrite in ACN at elevatedtemperature (Method J) to afford compounds of formula xxxiv.

Schemes 9-21 describe methods for the introduction of R¹ and W—R^(A)groups.

4-Alkoxy thiophenes/thiazoles can be obtained by the conventionalalkylation method of 4-hydroxythiazole derivatives obtained in scheme 4.As shown in scheme 9,4-hydroxy thiophenes/thiazoles xviii can be treatedwith alkyl halides using a suitable base, such as potassium carbonate,in a suitable solvent, for example DMF, at elevated temperature toafford compounds of formula xxxv (Method R).

Scheme 10 shows a general route for introducing halogen functionality atthe 4-unsubstituted position of thiophene/thiazole core.

Halogenation of thiophene/thiazoles can be achieved in a similar manneras reported in the literature (Takami et al, Tetrahedron 2004, 60,6155). For example, xxxvi is treated with a generally known halogenatingreagent, such as bromine or N-bromosuccinimide, in a suitable solvent,such as DCM, at elevated temperature to afford compounds of formulaxxxvii (Method C).The halogenated thiazole xxxvii can be used for further functional grouptransformation shown below.

Scheme 11 shows general methods for the synthesis of 4-aminothiazolederivatives xxxix from 4-halogenated thiazoles xxxviii, which can beprepared by the procedure described in scheme 10. Displacement of ahalogen group with an amine can be achieved in a similar manner asreported in the literature (J. Med. Chem 2006, 49, 5769). Treatment ofxxxviii with an amine at elevated temperature in a suitable solvent,such as DMF, can lead to amines xxxix (Method S). If necessary a base,such as sodium carbonate, can be added.

As shown in Scheme 12, carbon functionality can be introduced by thewell known cross-coupling technique from the 4-halogenatedthiophenes/thiazoles xxxvii which can be prepared by the proceduredescribed in scheme 10.

For example, xv can be obtained from 4-halogenated thiophenes/thiazolesxxxvii by reaction with an organic boronic acid reagent, or an organiczinc reagent in a presence of palladium catalyst. Suzuki couplings withalkyl, alkenyl boronic acids or esters can be performed using Pd(PPh₃)₄,or a similar palladium catalyst, a suitable base, such as sodiumcarbonate in an appropriate solvent, such as DME/water, at elevatedtemperature (Method L), while Pd(tBu₃P)₂ can be used for Negishicoupling reactions, together with in a suitable solvent, such as THF, atelevated temperature (Method T).

Scheme 13 shows a general method for the synthesis carbon substitutedthiophenes/thiazoles. 4-halogenated thiophenes/thiazoles xxxvii can betreated with an alkyne in the presence of a suitable catalyst, forexample Pd(PPh₃)₄, CuI, base, such as TEA in a suitable solvent, likeDCM, to afford alkynes xli (Method U). Compounds xli can be then reducedto alkyl substituted thiophenes/thiazoles xlii, for example usinghydrogenation with Pd/C in a suitable solvent, such as ethanol (MethodV)

Scheme 14 shows a general method for the synthesis of carbon substitutedthiophenes. Halogenated thiophenes xxxvii can be treated withalkyllithium, arryllithium or alkylmagnesium reagents, such as of n-BuLiat low temperature to generate intermediate metallated thiophenes thatare subsequently treated with aldehydes or ketones to afford carbinolsxliii (Method W).

Scheme 15 shows a general method for the synthesis carbon substitutedthiophenes/thiazoles. Halogenated thiophenes/thiazoles xxxvii can betreated with vinylorganometallic reagents, for examplevinyltributylstannane under Stille conditions (Method K), orvinyltrifluoroborate under Suzuki conditions (Method L) to afford vinylthiophenes/thiazoles, that can be oxidized to aldehydes xliv using asuitable method, for example OsO₄, sodium periodate in water-dioxanemixture (Method X). Aldehydes xliv can be then treated withorganometallic reagents, such as Grignard or alkyl/aryllithium compoundsin a suitable solvent, such as THF, at low temperature to affordcarbinols of formula xlv (Method Y).

Scheme 16 shows a general method for the synthesis of alcohols xlvi andethers xlvii. Aldehydes prepared as described in Scheme 15 above can betreated with a suitable reducing agent, such as NaBH₄ in an appropriatesolvent, for example THF, to afford alcohols of formula xlvi (Method Z).Alcohols xlvi can be then alkylated using standard conditions, forexample with alkyl halides in the presence of base, such as K₂CO₃, inTHF to afford ethers xlvii (Method AA).

Scheme 17 shows a general method for the synthesis of amines xlviii. Asshown is Scheme 17, alcohols can be activated via sulfonyl esters, forexample by reaction with methanesulfonic chloride and a base, such aspyridine in a suitable solvent, for example DCM. Sulfonyl esters arethen treated with amines at elevated temperature to provide targetamines xlviii (Method AB).

Scheme 18 shows a general method for the synthesis of ethers it whenW^(L) is an aromatic or heteroaromatic group. As shown is Scheme 18,alcohols xlv are treated with an excess of alcohol, such as methanol, inthe presence of an acid, like aqueous HCl with an optional co-solvent,for example dioxane at ambient temperature to afford ethers of formulail.

As shown in Scheme 19, sulfur functionality can be introduced to the4-halogenated thiazoles/thiophenes xxxvii by a similar manner asdescribed by Rossignol et al, US2009036467. Treatment of xxxvii withthiols in the presence of a copper catalyst, like CuI in a suitablesolvent, such as DMF, with an appropriate base, for example sodiumhydroxide, at elevated temperature gives thioethers of formula I (MethodAD). Thioethers l can subsequently be oxidized to sulfones li using asuitable oxidating agent, for example mCPBA in DCM (Method AE).

As shown in Scheme 20, amine or amide functionality can be introduced bythe well known palladium catalyzed amination amidation reaction, socalled Buchwald coupling, to the 4-halogenated thiophenes/thiazolesxxxvii.

For example, halides xxxvii can be treated with amines using anappropriate Pd catalyst, such as Pd₂dba₃/BINAP, with a suitablesolvent/base combination, for example NaOtBu in toluene at elevatedtemperature or using microwave irradiation to afford amines of formulaIII (Method AF).Coupling with amides also can be carried out using a suitable Pdcatalyst, for example Pd₂dba₃/XantPhos, with a suitable solvent/basecombination, like Cs₂CO₃ in dioxane at elevated temperature or usingmicrowave irradiation to give amides of formula liii (Method AG).

As shown in Scheme 21, 4-hydroxythiazoles or thiophenes xviii can betransformed to various functionalized thiazole thiophene derivatives viatriflate liv.

For example, compounds xviii can be transformed into triflates liv,using, e.g., triflic anhydride, with pyridine as base in DCM (Method U).Triflates liv can be then subjected to coupling reactions with amines,boronic esters, stannanes, or thiols under similar conditions asdescribed for analogous halides in Schemes 11-14 (analogous literatureexamples include Rzasa, R. et al, Bioorg. Med. Chem. 2007, 15, 6574;Langille, N. F., Org. Lett. 2002, 4, 2485.) to afford compounds offormula lv.

Scheme 22 shows a general route for introducing halogen functionalityonto unsubstituted 5-position of thiophene/thiazole core scaffold.

Halogenation of 5-unsubstituted thiazoles/thiophenes can be achieved ina similar manner as reported in the literature (Haelmmerle et al,Synlett 2007, 2975). For example, lvi is treated with a generally knownhalogenating reagent such as bromine or N-bromosuccinimide in a suitablesolvent, such as DCM to afford compounds of formula lvii (Method AI).The resulting halogenated thiophenes/thiazoles lvii can be used for thefurther functional group transformation reaction such as described inscheme 11-15.

Scheme 23 shows a general route for preparing amide compounds of formulalix. As shown in Scheme 23, acids lviii may be treated with amines usingstandard coupling conditions, such as EDCI and HOBt in DCM to affordamides lix (Method AJ).

When ammonia is used as an amine source, primary amide derivatives lxmay be obtained, which can be used as intermediates for the constructionof azoles as described in Schemes 25, 26, 28 and 37.

As shown Scheme 24, 5-halogenated thiophenes/thiazoles lvii can beprepared by the Hunsdiecker reaction from thiophene thiazole carboxylicacid analogs lviii.

As shown in Scheme 24, acids xlviii may be treated with sliver hydroxideto form a silver salt, which is subsequently treated with halogen, forexample bromine, in a suitable solvent, such as CCl₄ at elevatedtemperature to form lvii (Method AK).

As shown in scheme 25, amides lx, which can be prepared by the proceduredescribed in scheme 23, are treated with phosphoryl chloride, or similarreagents to form 5-cyano thiophenes thiazoles of formula lxiv (MethodAL).

As shown in scheme 26, amides lx, which can be prepared by the proceduredescribed in scheme 23, are treated with a suitable reagent, for exampleLawesson's reagent, or P₂S₅ in a suitable solvent, such as toluene atelevated temperature to afford thioamides of formula lxv (Method AM).

As shown in scheme 27, 5-cyano thiazoles/thiophenes lxiv, which can beprepared by the procedure described in scheme 25, are treated with asuitable reagent, for example ammonium sulfide in a suitable solvent,such as methanol to afford thioamides of formula lxv (method AN).

In the schemes 28-46, general procedures for the construction of therepresentative azoles as R¹ are described.

Schemes 28-30 describe the formation of 1,2,4-triazolyl group as R¹.

As shown in Scheme 28, amides lx, which can be prepared by the proceduredescribed in scheme 23, can be treated with DMF-DMA at elevatedtemperature or under microwave irradiation (Method BA) to giveintermediate amidines lxvi that are transformed to 1,2,4-triazoleslxvii′ and lxvii″ using hydrazine or substituted hydrazines in aceticacid at elevated temperature or under microwave irradiation (Method BB).

As shown in Scheme 29, 1,2,4-triazoles lxvii, which can be prepared bythe procedure described in scheme 28, are treated with a suitablehalogenating agent, like NBS, in a suitable solvent, for exampletetrachloromethane, to afford compounds of formula lxviii (Method C).

As shown in Scheme 30, acids lviii may be coupled with cyanamide, forexample via an intermediate acid halide in a suitable solvent, such asDCM to acylcyanamides lxix (Method BC), that are in turn treated withhydrazine using appropriate conditions, for example acetic acid atelevated temperature to give compounds of formula lxx (Method BD).

Scheme 31-39 describes the formation of 2-imidazolyl group as R¹.

As shown in Scheme 31, acids lviii are treated with Boc protectedethylenediamine using standard coupling conditions, such as EDCI andHOBt in DCM (Method AJ). Protective group is removed using anappropriate acid, for example TFA in DCM to give amide lxxi (Method I).Cyclization of lxxi is achieved using suitable conditions, for examplePOCl₃ (Method BE) to form dihydroimidazoles lxxii. Dihydroimidazoleslxxii can be oxidized to imidazoles lxxiii using a suitable oxidativemethod, for example heating with Magtrieve (Method BF).

Scheme 32 above shows an alternative route for preparing imidazoles offormula lxxiii. As shown in Scheme 32, acids lviii are treated withamines using standard coupling conditions, such as EDCI and HOBt in DCMto afford amides lxxv (Method AJ). Cyclization to imidazoles may beachieved through a 3-step one pot process that involves treatment withphosphorus pentachloride and HCl in dioxane to afford carbimidoylchloride intermediates lxxvi, that can be then treated withaminoacetaldehyde dimethylacetal followed by HCl in dioxane at elevatedtemperature to give lxxiii (Method BG). When R^(3′)=allyl, benzyl orsubstituted benzyl, it can also serve as a protecting group.

As shown in scheme 33, aldehydes lxxvii may be condensed with dicarbonylcompounds, such as diketones, ketoaldehydes, or glyoxal with anappropriate ammonia source, such as ammonium acetate, with suitableacid, such as acetic acid in solvent such as methanol to form imidazoleslxxiii (Method BH).

As shown in scheme 34, aldehydes of formula lxxvii can be treated withalpha, alpha-dihalo-ketones under suitable conditions, such as ammoniumhydroxide, sodium acetate in an appropriate solvent, for examplemethanol and water to afford imidazoles of formula lxxiii (Method BI).

As shown in scheme 35, treatment of nitriles lxiv, which can be preparedby the procedure described in scheme 25, with LiHMDS in a suitablesolvent mixture, such as THF/ether/hexane gives amidines of formulalxxviii (Method BJ) that can be treated with haloketones in the presenceof a suitable base, such as potassium carbonate in an appropriatesolvent, such as DCM under elevated temperature to give imidazoles ofgeneral formula lxxiii (Method BK).

As shown in scheme 36, treatment of thioamides lxv, which can beprepared by the procedure described in scheme 26 or 27, with methyliodide affords imidothioate intermediates lxxix (Method BL), which maythen be treated with optionally substituted aminoacetaldehyde dimethylacetal in a suitable solvent, like acetic acid, at elevated temperatureto afford intermediate amidines lxxx (Method BM). Amidines lxxx can thenbe treated with an acid, such as aqueous HCl and a suitable co-solvent,like ethanol, at elevated temperature to give imidazoles of formulalxxiii (Method BN).

As shown in scheme 37, treatment of amides lx, which can be prepared bythe procedure described in scheme 23, with an alkylating agent, such asMeerwein's reagent, in DCM (Method BO) gives iminoesters lxxxi, whichcan be then treated with diamines using appropriate conditions, forexample ethanol at elevated temperature (Method BP) to formedihydroimidazoles lxxii, which can be then oxidized in a same manner asin Method BF described in Scheme 31, or when R⁴ is an appropriateleaving group, elimination can be carried out using a base, such as DBUin DCM (Method BQ).

As shown in Scheme 38, acids lviii may be transformed to ketones lxxxiiusing a suitable synthetic sequence, for example through a coupling withN,O-dimethylhydroxylamine and subsequent treatment of the resultingWeinreb amides with alkyllithium or Grignard reagents in a suitablesolvent, like THF (Method BR).

Ketones lxxxii are then halogenated with a suitable reagent, such asbromine or NBS in an appropriate solvent, like DCM (Method C) to formalpha-halogenated ketones lxxxiii (X=halogen). Alternatively, treatmentof ketones lxxxii with a suitable oxidative sulfonylating agent, likehydroxy(tosyloxy)iodobenzene using suitable conditions, for exampleheating in acetonitrile (Method AS) affords sulfonyl esters of formulalxxxiii (X═OSO₂R).Treatment of lxxxiii with amidine reagents in the presence of a suitablebase, like potassium carbonate in a suitable solvent, such as THF-watermixture at elevated temperature or microwave irradiation affords thefinal imidazoles lxxxiv′ and lxxxiv″ (Method BT). Alternatively,compounds lxxxiii can be treated with large excess of amides, such asformamide using microwave irradiation to afford imidazoles lxxxiv′ andlxxxiv″ (Method BU).

As shown in scheme 39, treatment of nitriles lxiv, which can be preparedby the procedure described in scheme 25, with isocyanates in thepresence of a suitable base, such as tOBuK, in a suitable solvent, forexample THF gives imidazoles of formula lxxxiv″′. (Method BV).

As shown in scheme 40, treatment of aldehydes lxxvii withN,N-dimethylsulfonamide at elevated temperature in a suitable solvent,for example toluene, to allow azeotropic removal of water can affordintermediate imines, that are treated with TOSMIC, a suitable base, likepotassium carbonate in a suitable solvent, such as DME at elevatedtemperature to afford intermediate imidazole sulfonamides, that can behydrolyzed to imidazoles lxxxiv with an acid, for example aqueous HBr atelevated temperature (Method DC).

Schemes 41 and 42 describe the procedures for introducing a pyrazolylgroup.

As shown in Scheme 41, ketones lxxxii, which can be prepared by theprocedure described in scheme 38, are treated with DMF-DMA to afford anintermediate enamines (Method BA) followed by reaction with substitutedhydrazine, or hydrazine hydrate in a suitable solvent, for exampleacetic acid, to give pyrazoles lxxxv (Method BB).

As shown in Scheme 42, halides lvii, which can be prepared by theprocedure described in scheme 24, are treated with heteroaryl boronicacids or esters, in the presence of a suitable catalyst, for examplePd(PPh₃)₄, using a base, such as cesium carbonate in a suitable solvent,like dioxane-water mixture at elevated temperature to afford compoundsof formula lxxxvi (Method L).

As shown in Scheme 43, alkynes lxxxviii, which can be prepared by theknown Stille- or Sonogashira-coupling reaction in which a halide lvii,which can be prepared by the procedure described in scheme 24, and anappropriate alkyne derivative may be treated with azides, inorganic ororganic a suitable solvent, such as dioxane, at elevated temperature toafford triazoles of formula lxxxix and lxxxix′ (Method BW).

As shown in Scheme 44, amides lx, which can be prepared by the proceduredescribed in scheme 23, may be treated with an azide source, for examplesodium azide using a suitable Lewis acid, for example silicontetrachloride in an appropriate solvent, such as acetonitrile to givetetrazoles xc (Method BX).

As shown in scheme 45, thioamides lxv, which can be prepared by theprocedure described in scheme 26 or 27, are treated with substitutedbromoacetaldehyde dimethyl acetals to afford thiazoles of formula xci(Method BY).

As shown in scheme 46, alpha-halogenated ketones lxxxiii, which can beprepared by the procedure described in scheme 38, may be treated withformamide under elevated temperature or microwave irradiation to affordthe final 4-oxazoles xcii (Method BZ).

As shown in scheme 47, acids lviii are coupled with acylhydrazines usingstandard coupling conditions, such as EDCI, HOBt, DMF at elevatedtemperature to afford intermediates xciii (Method AJ), that are treatedwith Lawesson's reagent using suitable conditions, for example intoluene under reflux to afford thiadiazoles xciv (Method CA).

Scheme 48-51 describe general procedure for the functional grouptransformation on HY.

Scheme 48 shows a general route for the transformation of2-fluoropyridyl to 2-substituted aminopyridyl to give the compounds offormula xcvi.

As shown in Scheme 48, compounds xcv can be treated with amines atelevated temperature or under microwave irradiation to give2-aminopyridines xcvi (Method CB).

Scheme 49 shows a general route for the transformation of 2-halopyridylto 2-acylaminopyridyl by Buchwald reaction to give the compounds formulaxcviii.

As shown in Scheme 49, compounds xcvii can be treated with amides orcarboxamides in the presence of a suitable catalyst, such as Pd₂ dba₃,XantPhos, base like cesium carbonate in an appropriate solvent, forexample dioxane at elevated temperature or under microwave irradiationto give acylaminopyridines xcviii (Method AG).

As shown in Scheme 50, compounds is can be coupled with stannanes undersuitable conditions, for example Pd(PPh₃)₄, CuI, LiCl in dioxane atelevated temperature to give compounds c (Method K).

Oxidation of thioethers c to sulfones ci can be achieved using asuitable oxidant, for example mCPBA in DCM (Method CC).Methanesulfonyl group of sulfones ci can be displaced by treatment withamines in a suitable solvent, for example THF to afford2-aminopyrimidines cii (method H).

Scheme 51 shows a general route for the transformation of 4-pyridyl to2-halo-4-pyridyl compounds formula xcvii.

As shown in Scheme 51, compounds ciii can be treated with an oxidant,for example mCPBA in a suitable solvent, such as DCM to affordintermediate N-oxides civ (Method CD), which may be halogenated in2-position using phosphoryl halides, for example phosphoryl chloride,under elevated temperature to afford compounds of formula xcvii (MethodCE).

Schemes 52-58 describe the procedures for the synthesis of buildingblocks for HY.

Scheme 52 shows a general method for the synthesis ofimidazo[1,2-a]pyridines cvi. As shown in Scheme 52, 2-aminopyridines cvmay be condensed with alpha-halogenated beta-ketoesters in a suitablesolvent, for example ethanol, at elevated temperature to affordintermediate esters, that are hydrolyzed using standard conditions, suchas aqueous sodium hydroxide in THF followed by acidic workup to giveacids cvi (Method CF).

Scheme 53 shows a general method for the synthesis ofimidazo[1,2-b]pyridazines cviii. As shown in Scheme 53,2-aminopyridazines cvii may be condensed with α-halogenatedbeta-ketoesters in a suitable solvent, for example ethanol at elevatedtemperature to afford intermediate esters, that are hydrolyzed usingstandard conditions, such as aqueous sodium hydroxide in THF followed byacidic workup to give acids cviii (Method CG).

Scheme 54 shows a general method for the synthesis ofimidazo[2,1-b][1,3]thiazoles cx. As shown in Scheme 54, 2-aminothiazolescix may be condensed with α-halogenated β-ketoesters in a suitablesolvent, for example ethanol, at elevated temperature to affordintermediate esters, which may be hydrolyzed using standard conditions,such as aqueous sodium hydroxide in THF followed by acidic workup togive acids cx (Method CH).

Scheme 55 shows a general method for the synthesis ofpyrazolo[1,5-a]pyridines cxiii. As shown in Scheme 55, pyridines cxi maybe N-aminated with a suitable agent, such asO-(mesitylsulfonyl)hydroxylamine using appropriate conditions, forexample toluene or ethyl acetate as solvent (Method CI).

Resulting N-aminopyridinium salts cxii may then be condensed withalkynylcarboxylic acid esters with a suitable base, such as potassiumcarbonate in a suitable solvent, for example DMF to afford intermediateesters, which may be hydrolyzed using standard conditions, such asaqueous sodium hydroxide in THF followed by acidic workup to give acidscxiii (Method CJ).

Scheme 56 shows a general method for the synthesis ofpyrazolo[5,1-b][1,3]thiazoles cxvii. As shown in Scheme 56,2-methylthiazoles cxiv may be N-aminated with a suitable agent, such asO-(mesitylsulfonyl)hydroxylamine using appropriate conditions, forexample toluene or ethyl acetate as solvent (Method CI).

Resulting N-aminothiazolium salts cxv can then be condensed with aceticanhydride and potassium acetate at elevated temperature to afford methylketone intermediate cxvi (Method CJ), which can be converted tocarboxylic acid cxvii moiety by well known functional transformation ofmethyl ketone to carboxylic acid.

Scheme 57 shows an alternative method for the synthesis ofpyrazolopyridines cxix. As shown in Scheme 57, halides is are treatedwith alkynyl stannanes in the presence of a suitable catalysts, such asPd(PPh₃)₄, CuI, with LiCl in an appropriate solvent, like dioxane atelevated temperature to give alkynes of formula cxviii (Method CK).Alkynes cxviii are then coupled with N-aminopyridinium salts with abase, like potassium carbonate in a suitable solvent, for example DMF toafford compounds of formula cxix (Method CJ).

Scheme 58 shows an alternative method for the synthesis ofimidazolopyridines cxxiii. As shown in Scheme 58, 2-methylthiazoles cxxmay be deprotonated with a suitable reagent, such as n-BuLi andsubsequently treated with Weinreb amides in a suitable solvent, such asTHF to give ketones cxxi (Method CL). Halogenation of ketones can beachieved using standard conditions, for example NBS in DCM (Method C)and the resulting haloketones cxxii are then treated with aminopyridinesin a suitable solvent, for example ethanol at elevated temperature togive compounds of formula cxxiii (Method CF).

Scheme 59 shows a general method for the synthesis of bicyclic lactambuilding blocks cxxix and cxxx. As shown in Scheme 59, substituted2-chloro-4-fluoropyridines can be amidated, for example with BocNH₂, Pd₂dba₃ and a suitable ligand, such as X-Phos in the presence of a base,for example cesium carbonate in an appropriate solvent, like dioxane toafford Boc-protected 2-aminopyridines cxxv (Method AG). Compounds cxxvcan be deprotonated, for example using n-BuLi/TMEDA in THF at lowtemperature (Method M) and then quenched with a molecule of halogen,such as iodine in THF (Method N) to give halogenated compounds cxxvi.Compounds cxxvi can be coupled with diethoxypropene using a suitable Pdcatalyst, such asDi-mu-chlorobis[5-hydroxy-2-[1-(hydroxyimino-kappaN)ethyl]phenyl-kappaC]palladium(II)dimer with an appropriate base, like N,N-diisopropylethylamine in asuitable solvent, for example DMF-water mixture (Method CM) to affordlactams of formula cxxvii. Transformation of fluoro cxxvii into hydroxylanalogs cxxviii can be carried out using a standard procedure, forexample treatment with benzyl alcohol in the presence of a base, such assodium hydride at elevated temperature and subsequent debenzylation,such as using hydrogenation with Pd/C catalyst in a suitable solvent,such as ethanol (Method CN). Triflates cxxix can be formed by treatmentof cxxviii with a suitable reagent, for example triflic anhydride usingappropriate conditions, such as pyridine as a base in DCM (Method AH).Triflates cxxix can be coupled with stannanes xxix, obtained in Scheme 6using standard Stille conditions (Method K). Alternatively, triflatescxxix can be transformed into stannanes cxxx using a suitable method,such as heating with hexamethyldistannane, Pd(PPh₃)₄ in a suitablesolvent, like THF (Method CO). Stannanes cxxx can be then coupled withthiophene/thiazole halides ic, which can be prepared by the proceduresdescribed in schemes 3, 5, 6 using standard Stille conditions (MethodK).

Scheme 60 shows an alternative method for the synthesis of bicycliclactam building blocks cxxxv. As shown in Scheme 60, compounds cxxxi canbe deprotonated with a suitable reagent, such as n-BuLi in THF at lowtemperature (Method M) and then treated with DMF to producecarbaldehydes cxxxii (Method CP). Aldehyde group in cxxxii can be thentreated with enolate generated from t-Butylacetate and LDA in a suitablesolvent, such as THF at low temperature (Method CR) to form intermediateβ-hydroxyesters cxxxiii that can be cyclized to lactams cxxxiv using anacid, such as HCl, in water at elevated temperature (Method CS). Halidescxxxiv can be coupled with stannanes xxix, obtained in Scheme 6 usingstandard Stille conditions (Method K). Alternatively, transformation ofaryl halides cxxxiv to stannanes cxxxv can be carried out usinghexamethyldistannane, Pd(PPh₃)₄ in a suitable solvent, like THF (MethodCO). Stannanes cxxxv can be then coupled with thiophene/thiazole halidesic, which can be prepared by the procedures described in schemes 3, 5, 6using standard Stille conditions (Method K).

Scheme 61 shows a general method for preparation of compounds of formulacxxxvii. As shown in scheme 61, 2-halothiazoles are treated with aminesat elevated temperature, either neat, or in a suitable solvent, such asNMP with an appropriate base, for example K₂CO₃ (Method H) to afford2-aminothiazoles cxxxvi, that can be further transformed to compoundscxxxvii using generally known methods.

Scheme 62 shows a general method for preparation of compounds of formulacxxxix and cxli. As shown in Scheme 62, compounds xxxi can be coupledwith vinylstananes under suitable conditions, for example Pd(PPh₃)₄, CutLiCl in dioxane under elevated temperature to give alkenes cxxxviii(Method K), that can be further transformed to compounds cxxxix bygenerally known methods. Alternatively, hydrogenation of cxxxviii, forexample using Pd/C as catalyst in a suitable solvent, such as ethanol(Method V) can afford compounds cxl, that can be further transformed tocxli by generally known methods.

Scheme 71 shows a general method for the synthesis of amines xlviii. Asshown is Scheme 71, alcohols xlv can be transformed to halides xlv′using treatment with a suitable reagent, such as PCl₅ in a suitablesolvent, such as DCM. Halides xlv′ are then treated with amines atelevated temperature to provide target amines xlviii (Method AB).

Scheme 63 shows a general route for the synthesis of compounds offormula cl. Thioamide cxlii can be treated with alpha-halogenatedcarbonyl compounds cxliii in a suitable solvent, such as isopropanol atelevated temperature to give thiazoles cil. (Method F). A conversionreaction from cil to compounds cl can be performed by a combination ofgenerally known functional group conversion reactions.

Scheme 64 shows a general route for introducing morpholine to the2-position of thiazole core scaffold. Dihalothiazole esters, such asMethyl 2,4-dibromo-5-thiazolecarboxylate can be treated with morpholineat elevated temperature, with a suitable base, such as cesium carbonatein THF or other appropriate solvent (Method DA) to afford compounds offormula clii. Compounds clii can be then transformed into compoundscliii using generally known functional group conversion reactions.

Scheme 65 describes the procedure for the synthesis of 3-cyanothiophenesclix. Substituted alkoxyethenamine cliv can be treated withmalononitrile in the presence of a suitable base, such as TEA, in asuitable solvent, like chloroform, at elevated temperature to affordsubstituted aminoethylene malononitriles clv (Method P), that aretreated with sulfur under suitable conditions, such as DMF and elevatedtemperature, to give diaminocyanothiophenes xclvi (Method Q). Diaminesclvi may then be subjected to a Sandmeyer reaction using appropriatereagents, such as copper(II)bromide, amyl nitrite in ACN at elevatedtemperature (Method J) to afford compounds of formula clvii.Dihalocyanothiophenes can be then treated with morpholine at elevatedtemperature, with a suitable base, such as cesium carbonate in THF orother appropriate solvent (Method DA) to afford compounds of formulaclviii. Compounds clviii can be then transformed into compounds clvixusing generally known functional group conversion reactions.

Scheme 66 describes a procedure for the introduction of morpholine to3-cyanothiophene analogs. As shown in Scheme 66, sulfones of formula clx(synthetic examples given in Mansanet et al, WO 2005070916) can betreated with morpholine in a suitable solvent, e.g., THF, at elevatedtemperature (Method H) to give clxi. Conversion reactions from clxi tocompounds clix can be performed, for example, by a combination ofgenerally known functional group conversion reactions.

Scheme 67 shows a general method for preparation of compounds of formulaclxiv. As shown in Scheme 67, compounds clxii can be coupled withvinylstananes under suitable conditions, for example Pd(PPh₃)₄, CuI,LiCl in dioxane under elevated temperature to give alkenes clxiii(Method K). Alternatively, Suzuki conditions, such as Pd(PPh₃)₄, CsCO₃,dioxane at elevated temperature (Method L) can be used. Compounds clxiiican be then further transformed to compounds clxiv by generally knownmethods.

As shown in Scheme 68 carbon functionality can be introduced by the wellknown Negishi cross-coupling technique. Halogenated thiophenes/thiazolesclxv can be treated with alkyl zinc halides using Pd catalyst, such asPd(tBu₃P)₂ under standard Negishi coupling conditions, such as THF atelevated temperature (Method T) to afford compounds clxvi, that can befurther transformed to compounds clxvii using generally known methods.

As shown in Scheme 69, methyl substituent of thiophenes/thiazolesclxviii can be halogenated using a suitable reagent, for example NBSwith a radical source, such as AIBN in an appropriate solvent, like DCM(Method DB) to afford halides clxix. Halides clxix can be then coupledwith boronic acids or esters using the well known Suzuki cross-couplingtechnique, for example Pd(PPh₃)₄, Cs₂CO₃, dioxane-water at elevatedtemperature (Method L) to afford compounds clxvi, that can be furthertransformed to compounds clxvii using generally known methods.

As shown in Scheme 70, aldehydes or ketones clxx can be treated with2-Methyl-2-propanesulfinamide in the presence of a suitable Lewis acid,such as Ti(OiPr)₄ in anhydrous THF, or other suitable solvent to affordsulfinamides clxixi (Method DC), that can be subsequently treated withthiophene metal compounds clxxii (Method DD), obtained fromcorresponding thiophene halides through halogen-metal exchange, forexample from thiophene bromide using an excess of phenyllithium at lowtemperature. Formed sulfinyl amines clxxiii can be then treated with anacid, such as HCl in dioxane with an optional co-solvent, for exampleDCM (Method DE) to afford amino acids clxxiv.

As shown in Scheme 72, acyl halides can be coupled with thiomorpholineand alkylhaloacetate in the presence of a suitable base, such asdiisopropylamine in an appropriate solvent, for example MeCN at elevatedtemperature to afford cyanothiophenes clxxiii (Method DE). A conversionreaction from clxxiii to compounds clix can be performed by acombination of generally known functional group manipulations.

As shown in Scheme 73, compounds clxxiv (where W^(L) is an aromatic orheteroaromatic group) can be deprotonated using a suitable base, such asKOtBu in an appropriate solvent, for example THF and subsequentlyalkylated using an alkyl halide R⁷′-X (Method DF) to afford products ofbenzylic alkylations clxxv. Compounds clxxv can be further transformedto compounds clxxvi using generally known methods.

Scheme 74 shows a general route for the synthesis of compounds offormula clxxvii. Selenoamide can be treated with alpha-halogenatedcarbonyl compounds cxliii in a suitable solvent, such as isopropanol atelevated temperature to give selenazoles clxxvii. (Method F). Aconversion reaction from clxxvii to compounds clxxviii can be performedby a combination of generally known functional group manipulations.

As shown in Scheme 75, acyl halides can be coupled with selenomorpholinebuilding block and alkylhaloacetate in the presence of a suitable base,such as diisopropylamine in an appropriate solvent, for example MeCN atelevated temperature to afford selenophenes clxxix (Method DE). Aconversion reaction from clxxix to compounds clxxx can be performed by acombination of generally known functional group manipulations.

EXAMPLES

Table 1 below depicts certain compounds represented by compounds ofgeneral formula IA and IB.

TABLE 1

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

51

52

53

54

55

56

57

58

59

60

61

62

63

64

65

66

67

68

69

70

71

72

73

74

75

76

77

78

79

80

81

82

83

84

85

86

87

88

89

90

91

92

93

94

95

96

97

98

99

100

101

102

103

104

105

106

107

108

109

110

111

112

113

114

115

116

117

118

119

120

121

122

123

124

125

126

127

128

129

130

131

132

133

134

135

136

137

138

139

140

141

142

143

144

145

146

147

148

149

150

151

152

153

154

155

157

158

159

160

161

162

163

164

165

166

167

168

169

170

171

172

173

174

175

176

177

178

179

180

181

182

183

184

185

186

187

188

189

190

191

192

193

195

196

197

198

199

200

201

202

203

204

205

206

207

208

209

210

211

212

213

214

215

216

217

218

219

220

221

222

223

224

225

226

227

228

229

230

231

232

233

234

235

236

237

238

239

240

241

242

243

244

245

246

247

248

249

250

251

252

253

254

255

256

257

258

259

260

261

262

263

264

265

266

267

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DEFINITIONS

-   -   AcOH acetic acid    -   ACN acetonitrile    -   ATP adenosine triphosphate    -   br broad    -   BCA bicinchoninic acid    -   BSA bovine serum albumin    -   BOC tert-butoxycarbonyl    -   BuLi butyllithium    -   m-CPBA m-chloroperbenzoic acid    -   d doublet    -   dd doublet of doublets    -   DCE dichloroethane    -   DCM dichloromethane    -   DDQ 2,3-dichloro-5,6-dicyano-1,4-benzoquinone    -   DIPEA diisopropylethyl amine    -   DMAP N,N-dimethylaminopyridine    -   DME 1,2-Dimethoxyethane    -   DMEM Dulbecco's Modified Eagle's Medium    -   DMF N,N-dimethylformamide    -   DMF-DMA N,N-dimethylformamide dimethyl acetal    -   DMSO dimethylsulfoxide    -   DPPA diphenylphosphoryl azide    -   DTT dithiothreitol    -   dppf diphenylphosphinoferrocene    -   EDCI N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide        hydrochloride    -   EDTA ethylenediaminetetraacetic acid    -   EtOAc ethyl acetate    -   EtOH ethanol    -   FA formic acid    -   FBS fetal bovine serum    -   J coupling constant    -   h hours    -   Hz: hertz    -   HATU N,N,N′,N′-tetramethyl-o-(7-azabenzotriazole-1-yl)uronium        hexafluorophosphate    -   HBTU o-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium        hexafluorophosphate    -   HEPES N-(2-Hydroxyethyl)piperazine-N′-(2-ethanesulfonic acid)    -   HOBT 1-hydroxybenztriazole hydrate    -   HRMS high resolution mass spectrum    -   LAH lithium aluminum hydride    -   LCMS liquid chromatography mass spectrum    -   LDA lithium diisopropylamide    -   LiHMDS Lithium bis(trimethylsilyl)amide    -   m multiplet    -   m/z mass to charge    -   Me methyl    -   MeOH methanol    -   min minutes    -   MS mass spectrum    -   MTT methylthiazoletetrazolium    -   MWI microwave irradiation    -   NBS N-bromosuccinimide    -   PBS phosphate buffered saline    -   PKA cAMP-dependent protein kinase    -   rt room temperature    -   a singlet    -   t triplet    -   TEA triethylamine    -   TFA: trifluoroacetic acid    -   TFFA trifluoroacetic anhydride    -   THF tetrahydrofuran    -   TMB 3,3′,5,5′-Tetramethylbenzidine    -   TMEDA Tetramethylethylenediamine    -   q quartet    -   WST        (4-[3-(4-iodophenyl)-2-(4-nitrophenyl)-2H-5-tetrazolio]-1,3-benzene        disulfonate sodium salt)

The following analytical methods were used:

LCMS sectra were run on a Phenominex Luna 5 μm C18 50×4.6 mm column on aHewlett-Packard HP1100 using the following gradients:

Method Formic Acid (FA): Acetonitrile containing 0 to 100 percent 0.1%formic acid in water (2.5 ml/min for a 3 minute run).

Method Ammonium Acetate (AA): Acetonitrile containing 0 to 100 percent10 mM ammonium acetate in water (2.5 ml/min for a 3 minute run).

Chiral isomers were separated using chiral HPLC on a Chiralpak IC 250×25mm 5 micron column using hexane/ethanol/diethylamine orhexane/isopropyl/alcohol/ethanol/diethylamine as mobil phase. Absoluteconfigurations of the separated isomers were unknown, structures wereassigned arbitrarily.

NMR spectrum is shown by proton NMR, with tetramethylsilane as theinternal standard and using 300 MHz Bruker Avance spectrometer equippedwith a 5 mm QNP probe and 400 MHz Bruker Avance II spectrometer equippedwith a 5 mm QNP probe for the measurement; 6 values are expressed inppm.

Example 1 Synthesis ofN-{4-[4-(4-chlorobenzyl)-3-cyano-5-(4H-1,2,4-triazol-3-yl)-2-thienyl]pyridin-2-yl}acetamide(Compound 71) and2-(2-aminopyridin-4-yl)-4-(4-chlorobenzyl)-5-(4H-1,2,4-triazol-3-yl)thiophene-3-carbonitrile(Compound 12)

Step 1: Ethyl 3-amino-4-cyano-5-(methylsulfanyl)thiophene-2-carboxylate

A mixture of [bis(methylsulfanyl)methylene]malononitrile (40 g, 230mmol), ethylthioglycolate (29 g, 230 mmol) and TEA (24 mL, 173 mmol) inMeOH (600 mL) was allowed to stir at reflux for 2 h. The reactionmixture was allowed to cool overnight and the precipitate was filteredoff then washed with cold MeOH (3×50 mL) to give ethyl3-amino-4-cyano-5-(methylsulfanyl)thiophene-2-carboxylate (52.4 g, 99%).LCMS: (FA) ES+ 275.

Step 2: Ethyl 4-cyano-3-iodo-5-(methylsulfanyl)thiophene-2-carboxylate

Ethyl 3-amino-4-cyano-5-(methylsulfanyl)thiophene-2-carboxylate (10 g,41.3 mmol) was dissolved in acetonitrile (50 mL) under an atmosphere ofargon. Diiodomethane (11.6 mL, 0.144 mol) was added and the mixture washeated at 40° C. Isoamyl nitrite (12.1 g, 0.103 mol) was added and thereaction was allowed to cool to room temperature and stirred for 2hours. The mixture was cooled down to 0° C., diluted with hexane (50 mL)and the precipitate was filtered off, washed with 10:1hexane-acetonitrile mixture (10 mL), 3:1 hexane-ether (10 mL) and hexane(10 mL). The precipitate was dried to afford ethyl4-cyano-3-iodo-5-(methylsulfanyl)thiophene-2-carboxylate (6.90 g, 45%).LCMS: (FA) ES+ 354. ¹H NMR (400 MHz, CDCl₃) δ: 4.38 (q, 2H), 2.70 (s,3H), 1.40 (t, 3H).

Step 3: Ethyl 4-cyano-3-iodo-5-(methylsulfonyl)thiophene-2-carboxylate

Ethyl 4-cyano-3-iodo-5-(methylsulfanyl)thiophene-2-carboxylate (7.2 g,20.4 mmol) was dissolved in DCM (200 mL) and THF (100 mL) and m-CPBA(9.14 g, 40.8 mmol) was added. The reaction mixture was stirred at rtovernight. Sodium sulfite (5.14 g, 40.8 mmol) was added and the mixturewas stirred for 10 minutes followed by the addition of potassiumcarbonate (8.45, 61.2 mmol). The suspension was stirred at rt for 1 hourand filtered through celite, washed with DCM and the solvent wasevaporated to afford ethyl3-iodo-4-cyano-5-(methylsulfonyl)thiophene-2-carboxylate (6.80 g, 78%).LCMS: (FA) ES+ 386. ¹H NMR (400 MHz, CDCl₃) δ: 4.45 (q, 2H), 3.38 (s,3H), 1.43 (t, 3H).

Step 4: Ethyl4-cyano-5-[(2,4-dimethoxybenzyl)amino]-3-iodothiophene-2-carboxylate

Ethyl 4-cyano-3-iodo-5-(methylsulfonyl)thiophene-2-carboxylate (5.60 g,0.0145 mol) and 2,4-dimethoxybenzylamine (3.51 mL, 0.0234 mol) werecombined in tetrahydrofuran (100 mL) and stirred at 60° C. for 3 days.The reaction was concentrated in vacuo, diluted with dichloromethane andhexanes and the resultant precipitate was filtered to yield the titlecompound (5.56, 81%) as a yellow solid. LCMS: (FA) ES⁺ , 473. ¹H NMR(400 MHz, d₆-DMSO) δ: 9.05 (s, 1H) 7.10 (d, 1H, J=8.57 Hz), 6.60-6.50(m, 2H), 4.30 (s, 2H), 4.22-4.14 (m, 2H), 3.80 (s, 3H), 3.75 (s, 3H),1.26-1.21 (m, 3H).

Step 5: Ethyl 4-cyano-3,5-diiodothiophene-2-carboxylate

To a solution of ethyl4-cyano-5-[(2,4-dimethoxybenzyl)amino]-3-iodothiophene-2-carboxylate(4.50 g, 9.53 mmol) in dichloromethane (100 mL) at room temperature wasadded trifluoroacetic acid (22.5 mL, 292 mmol). The mixture was thenstirred at room temperature for 10 minutes. The solvent was evaporatedand the excess trifluoroacetic acid was removed by azeotroping withtoluene. The crude material was diluted with ethyl acetate, then treatedwith saturated sodium bicarbonate solution. The mixture was extractedwith ethyl acetate five times and the combined organic extracts weredried over anhydrous sodium sulfate, filtered and concentrated in vacuo.Column chromatography was performed to yield ethyl5-amino-4-cyano-3-iodothiophene-2-carboxylate (2.85 g, 88%). LCMS: (FA)ES⁺ , 323. ¹H NMR (400 MHz, d₆-DMSO) δ: 8.18 (s, 2H), 4.20-4.16 (m, 2H),2.50-2.48 (m, 3H). To a suspension of5-amino-4-cyano-3-iodothiophene-2-carboxylate (2.85 g, 8.85 mmol) inacetonitrile (46.2 mL) under argon was added diiodomethane (2.49 mL,31.0 mmol). The mixture was heated to 38° C. for 30 minutes, then amylnitrite (2.59 g, 22.1 mmol) was added dropwise over 5 minutes. Thereaction was slowly allowed to cool to room temperature then the mixturewas concentrated and column chromatography was performed to yield thetitle compound (3.20 g, 79%). LCMS: (FA) ES⁺ , 434. ¹H NMR (400 MHz,d₆-DMSO) δ: 4.33-4.27 (m, 2H), 2.51-2.47 (m, 3H).

Step 6: Ethyl5-[2-(acetylamino)pyridin-4-yl]-4-cyano-3-iodothiophene-2-carboxylate

To a solution of ethyl 4-cyano-3,5-diiodothiophene-2-carboxylate (0.473g, 1.09 mmol) and N-[4-(trimethylstannyl)pyridin-2-yl]acetamide (0.392g, 1.31 mmol) in dioxane (10.2 mL) was added lithium chloride (0.139 g,3.28 mmol), copper(I) iodide (0.0624 g, 0.328 mmol), andtetrakis(triphenylphosphine)palladium(0) (0.0947 g, 0.0819 mmol). Thereaction flask was evacuated and backfilled with argon, then thesolution was heated at 110° C. for 2 hours. The mixture was cooled toroom temperature and a mixture of dichloromethane and methanol was addeduntil almost all solids had dissolved. The suspension was filteredthrough celite and the filtrate was evaporated. Column chromatographywas performed to yield the title compound (0.312 g, 65%). LCMS: (FA)ES+442. ¹H NMR (400 MHz, d₆-DMSO) δ: 8.54-8.49 (m, 2H), 8.31 (s, 1H),4.38-4.32 (m, 2H), 2.13 (s, 3H), 1.36-1.29 (m, 3H).

Step 7: Ethyl5-[2-(acetylamino)pyridin-4-yl]-3-(4-chlorobenzyl)-4-cyanothiophene-2-carboxylate

To a solution of ethyl5-[2-(acetylamino)pyridin-4-yl]-4-cyano-3-iodothiophene-2-carboxylate(0.209 g, 0.474 mmol) in tetrahydrofuran (3.3 mL) was added4-chlorobenzylzinc chloride (0.50M solution in tetrahydrofuran, 1.89 mL,0.947 mmol) and bis(tri-t-butylphosphine)palladium(0) (0.0182 g, 0.0355mmol) under argon. The solution was stirred at 60° C. for 3 hours. Thereaction was allowed to cool to room temperature and then the solventwas evaporated in vacuo. Column chromatography was performed to yieldthe title compound (0.159 g, 76%). LCMS: (FA) ES⁺ , 440. ¹H NMR (400MHz, CDCl₃) δ: 8.66 (br s, 1H), 8.60 (br s, 1H), 8.38 (d, J=5.27 Hz,1H), 7.51-7.47 (m, 1H), 7.33-7.23 (m, 4H), 4.51 (s, 2H), 4.39 (q, J=7.03Hz, 2H), 2.24 (s, 3H), 1.39 (t, J=7.03 Hz, 3H).

Step 8:5-[2-(Acetylamino)pyridin-4-yl]-3-(4-chlorobenzyl)-4-cyanothiophene-2-carboxylicacid

To a solution of ethyl5-[2-(acetylamino)pyridin-4-yl]-3-(4-chlorobenzyl)-4-cyanothiophene-2-carboxylate(0.080 g, 0.18 mmol) in tetrahydrofuran (1.28 mL) and water (0.85 mL)was added lithium hydroxide (1.0M solution in water, 0.236 mL, 0.236mmol). The reaction mixture was stirred at room temperature for 16hours. The mixture was acidified to pH 6 using aqueous 1N HCl (0.300mL). The mixture was extracted with ethyl acetate. The combined organicextracts were washed with brine, and then dried over anhydrous sodiumsulfate, filtered and concentrated in vacuo. Column chromatography wasperformed to yield the title compound (0.058 g, 78%). LCMS: (FA) ES⁺ ,412. ¹H NMR (400 MHz, d₆-DMSO) δ: 10.72 (s, 1H), 8.46-8.41 (m, 2H),7.42-7.39 (m, 1H), 7.36-7.32 (m, 4H) 4.53 (s, 2H), 2.11 (s, 3H).

Step 9:5-[2-(Acetylamino)pyridin-4-yl]-3-(4-chlorobenzyl)-4-cyanothiophene-2-carboxamide

To a solution of5-[2-(acetylamino)pyridin-4-yl]-3-(4-chlorobenzyl)-4-cyanothiophene-2-carboxylicacid (0.0710 g, 0.172 mmol) in dichloromethane (5.0 mL) was addedN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.0991 g,0.517 mmol) and 1-hydroxybenzotriazole hydrate (0.0528 g, 0.345 mmol).The solution was stirred at room temperature for 30 minutes, then added33% ammonium hydroxide (33:67 ammonia:water, 0.298 mL, 3.45 mmol) wasadded. The solution was then stirred at room temperature for 16 hours,then the mixture was concentrated and column chromatography wasperformed to yield the title compound (0.031 g, 42%). LCMS: (FA) ES⁺ ,411. ¹H NMR (400 MHz, d₆-DMSO) δ: 10.79 (s, 1H), 8.50-8.46 (m, 2H), 8.14(br s, 1H), 7.85 (br s, 1H), 7.47-7.43 (m, 1H), 7.39-7.34 (m, 2H),7.29-7.24 (m, 2H), 4.41 (s, 2H), 2.12 (s, 3H).

Step 10:N-{4-[4-(4-chlorobenzyl)-3-cyano-5-(4H-1,2,4-triazol-3-yl)-2-thienyl]pyridin-2-yl}acetamide(Compound 71)

To a solution of5-[2-(acetylamino)pyridin-4-yl]-3-(4-chlorobenzyl)-4-cyanothiophene-2-carboxamide(0.030 g, 0.073 mmol) in toluene (0.75 mL) was added1,1-dimethoxy-N,N-dimethylmethanamine (0.0970 mL, 0.730 mmol), and themixture was stirred at 100° C. for 90 minutes. The mixture wasconcentrated and the residue was dissolved in acetic acid (0.75 mL).Hydrazine (0.0114 mL, 0.365 mmol) was added and the mixture was stirredat 100° C. for 1 hour. The mixture was concentrated and the residue wastreated with water. The precipitate was collected, washed with water anddried in a vacuum oven to yield the title compound (0.016 g, 48%). LCMS:(FA) ES⁺ , 435. ¹H NMR (400 MHz, d₆-DMSO) δ: 10.76 (s, 1H), 8.77 (s,1H), 8.54-8.46 (m, 2H), 7.50-7.47 (m, 1H), 7.37-7.26 (m, 4H), 4.63 (s,2H), 2.12 (s, 3H).

Step 11:2-(2-Aminopyridin-4-yl)-4-(4-chlorobenzyl)-5-(4H-1,2,4-triazol-3-yl)thiophene-3-carbonitrile(Compound 12)

To a solution ofN-{4-[4-(4-chlorobenzyl)-3-cyano-5-(4H-1,2,4-triazol-3-yl)-2-thienyl]pyridin-2-yl}acetamide(0.020 g, 0.046 mmol) in tetrahydrofuran (5.0 mL) was added sodiumhydroxide (1.0M solution in water, 2.0 mL, 2.0 mmol). The solution wasstirred at room temperature for 48 hours. The mixture was extracted withethyl acetate three times, and the combined organic extracts were thendried over anhydrous sodium sulfate, filtered and concentrated in vacuo.Column chromatography was performed to yield the title compound (0.007g, 30%). LCMS: (FA) ES⁺ , 393. ¹H NMR (400 MHz, d₆-DMSO) δ: 8.75 (s,1H), 8.07-8.03 (m, 1H), 7.36-7.26 (m, 4H), 6.83-6.79 (m, 1H), 6.78-6.76(m, 1H), 6.34-6.29 (m, 1H), 4.61 (s, 2H), 4.04 (s, 2H).

Compounds in the following table were prepared from the appropriatestarting materials in a method analogous to that of Example 1:

36 LCMS: (FA) ES+ 355, 357 74 LCMS: (FA) ES+, 412, 414. 143 LC/MS: (FA)ES+ 371; ES− 369 148 LCMS: (FA) ES+ 394 179 LC/MS: (FA) ES+ 467 180LC/MS: (FA) ES+ 444; ES− 442

Example 2 Synthesis of4-(4-[(4-chlorophenyl)(hydroxy)methyl)-5-(4H-1,2,4-triazol-3-yl)thiophen-2-yl]picolinonitrile(Compound 81)

Step 1: 3-Bromothiophene-2-carboxamide

3-Bromothiophene-2-carboxylic acid (63.61 g, 307.2 mmol) was weighedinto a 1 L round bottom flask equipped with reflux condenser and theflask was purged with argon. To this flask was added toluene (636.1 mL,5972 mmol) and thionyl chloride (44.82 mL, 614.4 mmol) at roomtemperature, and the resulting mixture was stirred for 3 h at 100° C.The reaction mixture was evaporated and the residue was azeotroped withtoluene (2×100 mL). The resulting residue was dissolved intetrahydrofuran (954.1 mL, 11760 mmol) then 10 M ammonia in water (170mL, 2500 mmol) was added slowly into the solution. The mixture wasstirred for 5 h at room temperature. Thin-layer chromatography showedcomplete reaction. The reaction mixture was rotovaped to remove THF andthe solid residue in water was filtered through a glass frit funnel thenwashed with water and dried under vacuum to give3-bromothiophene-2-carboxamide as a white solid (33.26 g, 52.5%). LCMS:(FA) ES+206.0, 208.0

Step 2: 3-(3-Bromothiophen-2-yl)-4H-1,2,4-triazole

3-Bromothiophene-2-carboxamide (33.2 g, 161 mmol) in1,1-dimethoxy-N,N-dimethylmethanamine (100 mL, 800 mmol) and toluene(100 mL, 900 mmol) was heated at 90° C. for 2 h. The solvent wasevaporated off and the residue was dissolved in acetic acid (183 mL,3220 mmol). Hydrazine (20 mL, 600 mmol) was added and the mixture washeated at 90° C. again. After 40 min, LCMS showed complete reaction. Thereaction mixture was evaporated to remove most of the acetic acid. Waterwas added and the precipitate was collected and dried in air overnightto afford 3-(3-bromothiophen-2-yl)-4H-1,2,4-triazole as a white powder(31.7 g, 85.6%). LCMS: (FA) ES+230.0, 232.0

Step 3: (4-Chlorophenyl)[2-(4H-1,2,4-triazol-3-yl)-3-thienyl]methanone

To a solution of 3-(3-bromo-2-thienyl)-4H-1,2,4-triazole (15.05 g, 65.41mmol) in Tetrahydrofuran (500 mL, 6000 mmol) was added dropwise 2.5MBuLi in hexanes (104 mL, 262 mmol) at −70° C. (internal temperature) andthe solution was stirred for 30 min at −78° C. A solution of4-chloro-N-methoxy-N-methylbenzamide (41.24 g, 206.6 mmol) intetrahydrofuran (80 mL, 1000 mmol) was then added dropwise into thesuspension. The resulting mixture was stirred for 60 min at −78° C.Ammonium chloride (17.49 g, 327.0 mmol) in water (100 mL, 6000 mmol) wasadded to the mixture at −78° C. and the mixture was stirred for 15 minbefore being warmed to rt. The organic layer was separated and theaqueous layer was extracted with EtOAc. The combined organic layers werewashed with brine, dried over sodium sulfate, and then filtered toremove drying agent. The solvent was evaporated and the residue waspurified by chromatography to afford(4-chlorophenyl)[2-(4H-1,2,4-triazol-3-yl)-3-thienyl]methanone as whitesolid (16.8 g, 88.5%). LCMS: (FA) ES+289.9, 291.8

Step 4:(4-Chlorophenyl)(2-(1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl)thiophen-3-yl)methanone

In a 500 mL, round bottomed flask,(4-chlorophenyl)[2-(4H-1,2,4-triazol-3-yl)-3-thienyl]methanone (16.89 g,58.29 mmol) was dissolved in tetrahydrofuran (500.0 mL, 6164 mmol). Tothe solution were added dihydropyran (31.9 mL, 3.50E2 mmol) andp-toluenesulfonic acid monohydrate (16.6 g, 87.4 mmol). The mixture wasstirred for 3 h at rt. The reaction was quenched by the addition ofsaturated aqueous solution of sodium bicarbonate (200 mL). The aqueousphase was separated and then extracted with EtOAc (300 mL). The combinedorganic phases were dried over anhydrous sodium sulfate. The dryingagent was removed by filtration and the filtrate was concentrated underreduced pressure. The residue was purified by chromatography to afford(4-chlorophenyl)(2-(1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl)thiophen-3-yl)methanoneas an oil which was dried under high vacuum overnight (19.4, 89.1%).LCMS: (FA) ES+374.2, 376.1.

Step 5:(5-Bromo-2-(1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl)thiophen-3-yl)(4-chlorophenyl)methanone

To a mixture of (4-chlorophenyl){2-[1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl]-3-thienyl}methanone(20.2 g, 54.0 mmol) in N,N-dimethylformamide (350 mL, 4500 mmol) wasadded dropwise a solution of N-bromosuccinimide (14.42 g, 81.05 mmol) inN,N-dimethylformamide (50 mL, 600 mmol) under argon. The mixture wasstirred at rt with care taken to block the reaction from exposure toambient light. After 3 h reaction, LCMS showed both starting materialand product. Additional N-bromosuccinimide (6.732 g, 37.82 mmol) wasadded and the mixture was stirred at rt again. After stirring overnight,the mixture was diluted with water and sodium bicarbonate solution andthen the mixture was extracted with EtOAc. The organic layer was washedwith water and brine. The EtOAc layer was dried and evaporated in vacuumto a residue, which was purified by chromatography to afford(5-bromo-2-(1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl)thiophen-3-yl)(4-chlorophenyl)methanoneas a white solid (18.0, 73.5%). LCMS: (FA) ES+ 451.9, 453.9

Step 6:(5-Bromo-2-(1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl)thiophen-3-yl)(4-chlorophenyl)methanol

To a solution of{5-bromo-2-[1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl]-3-thienyl}(4-chlorophenyl)methanone(11.81 g, 26.08 mmol) in tetrahydrofuran (300 mL, 4000 mmol) was addedlithium tetrahydroborate (52.17 mmol, 52.17 mmol) in tetrahydrofuran (26mL, 320 mmol) under argon. The mixture was stirred at rt for 3 h andthen cooled down in dry ice-acetone bath. Acetic acid (7.1 mL, 120 mmol)was added. The mixture was stirred for 5 min and saturated aqueoussodium bicarbonate solution was added, followed by EtOAc. The organiclayer was separated and washed with brine, then dried over sodiumsulfate. The solvent was removed and the residue was purified by columnchromatography to afford(5-bromo-2-(1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl)thiophen-3-yl)(4-chlorophenyl)methanolas a white powder (11.2, 94.2%). LCMS: (FA) ES+454.0, 456.0

Step 7:(4-chlorophenyl)(2-(1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophen-3-yl)methanol

To a mixture of{5-bromo-2-[1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl]-3-thienyl}(4-chlorophenyl)methanol(5.19 g, 11.4 mmol) in tetrahydrofuran (146.9 mL, 1811 mmol) was addedisopropylmagnesium chloride (1M in THF, 34.2 mL, 34.2 mmol) at −40° C.under argon. After addition, the reaction temperature was raised to rtfor 15 min. The mixture was then cooled to −78° C. and2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (8.149 mL, 39.94mmol) was added. After the addition, the mixture was brought to rt.After 1 h, the mixture was heated at 75° C. overnight. The mixture wascooled to rt and quenched with saturated ammonium chloride solution. Themixture was stirred for 10 min then extracted with EtOAc. The organiclayer was dried and evaporated in vacuum. The mixture was purified bychromatography to afford(4-chlorophenyl)(2-(1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophen-3-yl)methanolas a thick oil (5.32 g, 65.0%). LCMS: (FA) ES+502.2, 504.1.

Step 8: Potassium(4-((4-chlorophenyl)(hydroxy)methyl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl)thiophen-2-yl)trifluoroborate

To a suspension of(4-chlorophenyl)(2-(1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophen-3-yl)methanolin methanol (3.5 mL, 87 mmol) under argon was added potassium hydrogenfluoride (3.13 g, 40.0 mmol) in one portion at 0° C. Water (8.06 mL, 447mmol) was added dropwise. After the addition, the ice-water bath wasremoved and the mixture was stirred at rt over the weekend. The mixturewas evaporated and the residue was dried under high vacuum. The crudemixture was extracted with hot actone 3 times. The extracts werecombined and evaporated to dryness to afford potassium(4-((4-chlorophenyl)(hydroxy)methyl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl)thiophen-2-yl)trifluoroborateas a white powder (6.34 g, 100%). LCMS: (AA) ES− 442.2, 444.2, ¹H NMR(400 MHz, d₆-DMSO) δ: 8.71 (d, J=2.81 Hz, 1H), 7.35-7.24 (m, 2H), 7.45(td, J=4.77, 2.42, 2.42 Hz, 2H), 6.69-6.59 (m, 1H), 6.80 (d, J=4.16 Hz,1H), 5.81 (dd, J=4.74, 1.41 Hz, 1H), 5.57 (td, J=9.49, 2.15, 2.15 Hz,1H), 4.02-3.89 (m, 1H), 3.74-3.59 (m, 1H), 2.21-1.88 (m, 3H), 1.76-1.47(m, 3H).

Step 9:4-(4-((4-Chlorophenyl)(hydroxy)methyl)-5-(4H-1,2,4-triazol-3-yl)thiophen-2-yl)picolinonitrile(Compound 81)

A mixture of potassium(4-((4-chlorophenyl)(hydroxy)methyl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl)thiophen-2-yl)trifluoroborate(0.133 g, 0.276 mmol), 4-bromo-pyridine-2-carbonitrile (60.6 mg, 0.331mmol), 2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl (24.8mg, 0.0533 mmol), palladium acetate (4.6 mg, 0.020 mmol) and sodiumcarbonate (77 mg, 0.73 mmol) in ethanol (6.2 mL, 110 mmol) was degassedwith argon and then heated at 85° C. for 13 h. The mixture was absorbedon silica gel and purified by chromatography to afford an intermediate.LCMS: (AA) ES+478.1, 480.0. This intermediate in 1,4-dioxane (2.0 mL, 26mmol), tert-butyl alcohol (2.0 mL, 21 mmol) and 4.00 M HCl in dioxane(3.0 mL, 14 mmol) was heated at 60° C. for 1 h. The mixture wasevaporated to dryness and then purified by HPLC to afford4-(4-((4-chlorophenyl)(hydroxy)methyl)-5-(4H-1,2,4-triazol-3-yl)thiophen-2-yl)picolinonitrile(12.4 mg, 11.4%). LCMS: (FA) ES+ 394.3, 396.1. ¹H NMR (400 MHz, d₆-DMSO)δ: 14.69-13.48 (br, 1H), 8.69 (d, J=6.79 Hz, 2H), 8.45 (s, 1H),8.08-7.88 (m, 2H), 7.56 (d, J=8.39 Hz, 2H), 7.35 (d, J=8.40 Hz, 2H),6.79 (s, 1H).

Compounds in the following table were prepared from the appropriatestarting materials in a method analogous to that of Example 2:

3 LCMS: (AA) ES+ 394, 396. 8 LCMS: (FA) ES+ 399, 401. 10 LCMS: (AA) ES+408, 410. 13 LCMS: (AA) ES+ 425, 427. 16 LCMS: (AA) ES+ 387, 389. 17LCMS: (AA) ES+ 399, 401. 23 LCMS: (FA) ES+ 385, 387. 25 LCMS: (AA) ES+403, 405, 407. 42 LCMS: (AA) ES+ 419, 421. 48 LCMS: (AA) ES+ 394, 396.57 LCMS: (AA) ES+ 425, 427. 64 LCMS: (AA) ES+ 438, 440. 68 LCMS: (FA)ES+ 388, 390. 147 LCMS: (AA) ES+ 451, 453 197 LCMS: (AA) ES− 431, 433,435

Example 3 Synthesis of(4-chlorophenyl)[5-(2-fluoropyridin-4-yl)-2-(4H-1,2,4-triazol-3-yl)-3-thienyl]methanol(Compound 21)

Step 1:(4-Chlorophenyl){5-(2-fluoropyridin-4-yl)-2-[1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl]-3-thienyl}methanol

A mixture of{5-bromo-2-[1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl]-3-thienyl}(4-chlorophenyl)methanol(734 mg, 1.61 mmol), 2-fluoro-4-pyridinylboronicacid (455 mg, 3.23mmol), tetrakis(triphenylphosphine)palladium(0) (93.3 mg, 0.0807 mmol)and cesium carbonate (1.58 g, 4.84 mmol) in 1,4-dioxane (10.1 mL, 129mmol) and water (1.45 mL, 80.7 mmol) was irradiated in a microwave ovenat 140° C. under argon for 20 min. The reaction mixture was dry loadedonto silica gel and purified by column chromatography (SiO₂, elutionwith EtOAc in hexanes, 0-80% gradient) to afford(4-chlorophenyl){5-(2-fluoropyridin-4-yl)-2-[1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl]-3-thienyl}methanolas a white solid (0.71 g, 92.8%). LCMS: (AA) ES+ 471.1, 473.1

Step 2:(4-chlorophenyl)[5-(2-fluoropyridin-4-yl)-2-(4H-1,2,4-triazol-3-yl)-3-thienyl]methanol(Compound 21)

A mixture of(4-Chlorophenyl){5-(2-fluoropyridin-4-yl)-2-[1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl]-3-thienyl}methanol(0.261 g, 0.554 mmol), tert-butyl alcohol (3.9 mL, 41 mmol), 1,4-dioxane(2.6 mL, 33 mmol) and 4.00 M HCl in dioxane (3.66 mL, 16.6 mmol) washeated at 70° C. for 2 h. The mixture was cooled down. A small amount ofwater was added, followed by the addition of sodium bicarbonate (0.745g, 8.87 mmol). The mixture was stirred for 10 min and then evaporated invacuum. The residue was purified by (HPLC to afford4-chlorophenyl)[5-(2-fluoropyridin-4-yl)-2-(4H-1,2,4-triazol-3-yl)-3-thienyl]methanolas a white solid. LCMS: (AA) ES+ 387.2, 389.1; ¹H NMR (300 MHz,d₄-methanol) δ: 8.51 (s, 1H), 8.18 (d, J=5.41 Hz, 1H), 7.73 (s, 1H),7.60-7.44 (m, 3H), 7.37-7.23 (m, 3H), 6.76 (s, 1H).

Compounds in the following table were prepared from the appropriatestarting materials in a method analogous to that of Example 3:

11 LCMS: (AA) ES+ 383, 385. 14 LCMS: (AA) ES+ 403, 405, 407. 26 LCMS:(AA) ES+ 387, 389. 30 LCMS: (AA) ES+ 403, 405, 407. 34 LCMS: (AA) ES+387, 389. 40 LCMS: (AA) ES+ 403, 405, 407. 41 LCMS: (AA) ES+ 426, 428.43 LCMS: (AA) ES+ 383, 385. 45 LCMS: (AA) ES+ 387, 389. 52 LCMS: (AA)ES+ 369, 371. 55 LCMS: (AA) ES+ 370, 372. 59 LCMS: (AA) ES+ 370, 372. 69LCMS: (AA) ES+ 383, 385. 75 LCMS: (AA) ES+ 384, 386. 77 LCMS: (AA) ES+369, 371. 79 LCMS: (AA) ES+ 370, 372. 84 LCMS: (AA) ES+ 369, 371.

Example 4 Synthesis of4-[4-[(4-chlorophenyl)(methoxy)methyl]-5-(4H-1,2,4-triazol-3-yl)-2-thienyl]pyridine(Compound 6)

To a solution of(4-chlorophenyl)[5-pyridin-4-yl-2-(4H-1,2,4-triazol-3-yl)-3-thienyl]methanol(100 mg, 0.271 mmol) in methanol (10 mL) was added conc. HCl (2.0 mL, 24mmol) and the mixture was stirred at rt overnight. The reaction mixturewas concentrated and basified by sodium bicarbonate, loaded on silicagel and purified by column chromatography (SiO2, elution with 0-5% MeOHin DCM) to afford the title compound (80 mg, 78%). LCMS: (AA) ES+ 383.3,385.2; ¹H NMR (300 MHz, d₆-DMSO) δ: 8.70 (s, 1H), 8.57 (d, J=4.80 Hz,2H), 7.79 (s, 1H), 7.68 (d, J=4.79 Hz, 2H), 7.56 (d, J=8.25 Hz, 2H),7.38 (d, J=8.30 Hz, 2H), 6.50 (s, 1H), 3.31 (d, J=9.06 Hz, 3H).

Compounds in the following table were prepared from the appropriatestarting materials in a method analogous to that of Example 4:

220 LCMS: (AA) ES+ 440, 442.

Example 5 Synthesis of1-(4-chlorophenyl)-N,N-dimethyl-1-[5-pyridin-4-yl-2-(4H-1,2,4-triazol-3-yl)-3-thienyl]methanamine(Compound 9)

To a mixture of(4-chlorophenyl)[5-pyridin-4-yl-2-(4H-1,2,4-triazol-3-yl)-3-thienyl]methanol(141 mg, 0.382 mmol) (synthesized in an analogous way as described inExample 3) in methylene chloride (2.8 mL) was added pyridine (6.0 mL, 74mmol) and methanesulfonyl chloride (0.148 mL, 1.91 mmol) at 0° C. Afterthe addition, the mixture was warmed to rt and stirred for 30 min andthen heated at 60° C. for 20 min. The mixture was cooled in an ice bathand dimethylamine (0.553 mL, 11.5 mmol) in THF was added to the mixture.After the addition, the ice bath was removed and the mixture was stirredat rt for 30 min and then heated at 55° C. for 2 h. The mixture wascooled, concentrated, and the residue was purified by HPLC to afford1-(4-chlorophenyl)-N,N-dimethyl-1-[5-pyridin-4-yl-2-(4H-1,2,4-triazol-3-yl)-3-thienyl]methanamineas white powder (115 mg, 76%). LCMS: (AA) ES+ 396.3, 398.1; ¹H NMR (400MHz, d₆-DMSO) δ: 14.48-14.27 (m, 1H), 8.71 (s, 1H), 8.57 (dd, J=4.55,1.62 Hz, 2H), 7.95 (s, 1H), 7.73-7.63 (m, 4H), 7.39-7.30 (m, 2H), 5.53(s, 1H), 2.13 (s, 6H).

Compounds in the following table were prepared from the appropriatestarting materials in a method analogous to that of Example 5:

33 LCMS: (AA) ES+ 410, 412. 44 LCMS: (AA) ES+ 396, 398. 51 LCMS: (AA)ES+ 408, 410. 65 LCMS: (AA) ES+ 396, 398. 86 LCMS: (AA) ES+ 453, 455. 90LCMS: (AA) ES+ 465, 467 135 LCMS: (AA) ES+ 507, 509. 139 LCMS: (AA) ES+508, 510 146 LCMS: (FA) ES+ 520, 522 151 LCMS: (AA) ES+ 465, 467 152LCMS: (FA) ES+ 510, 512 154 LCMS: (FA) ES+ 494, 496 161 LCMS: (AA) ES+410, 412 163 LCMS: (AA) ES+ 508, 510 164 LCMS: (AA) ES+ 495, 497. 167LCMS: (AA) ES+ 476, 478 173 LCMS: (AA) ES+ 508, 510 176 LCMS: (AA) ES+465, 467 182 LCMS: (AA) ES+ 495, 497 183 LCMS: (AA) ES+ 496, 498. 185LCMS: (AA) ES+ 411, 413 192 LCMS: (AA) ES+ 509, 511. 196 LCMS: (AA) ES+536, 538 200 LCMS: (AA) ES+ 480, 482 201 LCMS: (AA) ES+ 481, 483 204LCMS: (AA) ES+ 453, 455 206 LCMS: (AA) ES+ 476, 478 208 LCMS: (AA) ES+508, 510 209 LCMS: (AA) ES+ 508, 510 212 LCMS: (AA) ES+ 495, 497. 216LCMS: (AA) ES+ 501, 503 221 LCMS: (AA) ES+ 529, 531 224 LC/MS: (FA) ES+572, 574; ES− 570, 572. 229 LCMS: (AA) ES+ 495, 497. 234 LCMS: (AA) ES+508, 510 240 LCMS: (AA) ES+ 507, 509 241 LCMS: (AA) ES+ 465, 467 242LCMS: (AA) ES+ 507, 509 243 LCMS: (AA) ES+ 458, 460 247 LCMS: (AA) ES+507, 509 248 LCMS: (AA) ES+ 495, 497 251 LCMS: (AA) ES+ 442, 444 254LCMS: (FA) ES+ 452, 454 259 LCMS: (AA) ES+ 509, 511. 261 LCMS: (AA) ES+453, 455 267 LCMS: (AA) ES+ 508, 510 268 LCMS: (AA) ES+ 509, 511. 270LCMS: (AA) ES+ 508, 510 283 LCMS: (AA) ES+ 509, 511.

Example 6 Synthesis of2-({4-[4-[(4-chlorophenyl)(hydroxy)methyl]-5-(4H-1,2,4-triazol-3-yl)-2-thienyl]pyridin-2-yl}amino)ethanol(Compound 49)

A mixture of(4-chlorophenyl){5-(2-fluoropyridin-4-yl)-2-[1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl]-3-thienyl}methanol(80.0 mg, 0.170 mmol), ethanolamine (0.104 g, 1.70 mmol) andN,N-diisopropylethylamine (0.118 mL, 0.679 mmol) in dimethylsulfoxide(0.5 mL, 7 mmol) was heated at 200° C. for 1 h under argon. The reactionmixture was cooled, diluted with water and extracted with butanol. Thebutanol layer was collected and evaporated to a residue which waspurified by chromatography (SiO₂, elution with 0-20% MeOH in DCM) toafford the intermediate. The intermediate in 1,4-dioxane (1.0 mL, 13mmol) and conc HCl (1.0 mL, 12 mmol) was stirred at rt for 1 h. Thesolvent was evaporated and the residue was purified by chromatography(SiO₂, elution with 0-70% (MeOH/DCM/NH4OH, 13852) in DCM) to afford2-({4-[4-[(4-chlorophenyl)(hydroxy)methyl]-5-(4H-1,2,4-triazol-3-yl)-2-thienyl]pyridin-2-yl}amino)ethanol(17.6 mg, 24.2%). LCMS: (AA) ES+ 428.2, 430.0; ¹H NMR (400 MHz, d₆-DMSO)δ: 14.66-14.13 (m, 1H), 8.68 (s, 1H), 7.94 (d, J=5.30 Hz, 1H), 7.58-7.48(m, 3H), 7.38-7.30 (m, 2H), 6.81-6.68 (m, 3H), 6.60 (s, 1H), 4.72 (s,1H), 3.57-3.45 (m, 2H), 3.34 (d, J=5.88 Hz, 3H).

Compounds in the following table were prepared from the appropriatestarting materials in a method analogous to that of Example 6:

28 LCMS: (AA) ES+ 435, 437. 62 LCMS: (AA) ES+ 398, 400.

Example 7 Synthesis of(4-methoxyphenyl)[5-pyridin-4-yl-2-(4H-1,2,4-triazol-3-yl)-3-thienyl]methanol(Compound 85)

Step 1: 3-(3-Bromo-5-iodo-2-thienyl)-4H-1,2,4-triazole

To a mixture of 3-(3-bromo-2-thienyl)-4H-1,2,4-triazole (1.12 g, 4.87mmol), iodine (1.12 g, 4.41 mmol) and periodic acid (4.80 g, 24.8 mmol)in acetic acid (11.0 mL, 200 mmol) were added water (8.0 mL, 400 mmol)and sulfuric acid (2.0 mL, 40 mmol) and the reaction mixture was stirredat rt for two days. The resulting white precipitate was collected byfiltration. The solid cake was washed with water and dried under highvacuum at 40° C. to yield product as a white solid (1.74 g, 100% yield,as a white solid). LCMS: (FA) ES⁺ , 357.7. ¹H NMR (400 MHz, d₆-DMSO) δ:8.63 (s, 1H), 7.43 (s, 1H)

Step 2:3-(3-Bromo-5-iodo-2-thienyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,2,4-triazole

Into a solution of 3-(3-bromo-5-iodo-2-thienyl)-4H-1,2,4-triazole (500.0mg, 1.40 mmol), N,N-dimethylaminopyridine (17.2 mg, 0.140 mmol) andN,N-diisopropylethylamine (0.32 mL, 1.83 mmol) in N,N-dimethylformamide(17.0 mL, 220 mmol) was added [13-(Trimethylsilyl)ethoxy]methyl chloride(0.270 mL, 1.55 mmol) was added and the solution was stirred for 2 h atrt. Water (5.0 mL) and EtOAc (5 mL) were added, the organic layer wasseparated, washed with brine, dried over MgSO₄, filtered, concentratedand the obtained residue was purified by column chromatography (SiO₂,elution with 0-30% EtOAc in hexane) to give the title compound as ayellowish oil (653 mg, (87% major isomer, 13% minor isomer) LCMS: (FA)ES⁺ , 486, 488. (major isomer) ¹H NMR (400 MHz, d₆-DMSO) δ: 8.81 (s,1H), 7.45 (s, 1H), 5.540-5.545 (s, br, 2H), 3.62-3.66 (m, 2H),0.840-0.880 (m, 2H), −0.05 (s, 9H). LCMS: (FA) ES⁺ , 486, 488. (minorisomer) ¹H NMR (400 MHz, d₆-DMSO) δ: 8.215 (s, 1H), 7.615 (s, 1H), 5.48(s, br, 2H), 3.44-3.50 (m, 2H), 0.75-0.80 (m, 2H), −0.08 (s, 9H).

Step 3:4-[4-Bromo-5-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,2,4-triazol-3-yl)-2-thienyl]pyridine

A mixture of3-(3-bromo-5-iodo-2-thienyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,2,4-triazole(653.0 mg, 1.34 mmol), pyridine-4-boronic acid (248 mg, 2.02 mmol),[1,1′-bis(diphenylphosphino)ferrocene]palladium(II)dichloride (55.2 mg,0.067 mmol) and cesium carbonate (1.80 g, 5.37 mmol) in 1,4-dioxane(8.40 mL, 107 mmol) and water (1.2 mL, 67.1 mmol) was heated at 110° C.under an atmosphere of argon overnight. Water (3 mL) and EtOAc (3 mL)were added, the organic layer was separated, washed with brine, driedover MgSO₄, filtered, concentrated and the obtained residue was purifiedby column chromatography (SiO₂, elution with 0-10% MeOH in DCM) to givethe title compound as a white solid (438 mg, 74.6%). LCMS: (FA) ES⁺ ,438, 440. ¹H NMR (400 MHz, d₆-DMSO) δ: 8.87 (s, 1H), 8.62-8.64 (dd,J=1.5 Hz, 2H), 7.98 (s, 1H), 7.30-7.75 (dd, J=1.5, 2H), 5.58-5.59 (s,br, 2H), 3.40-3.69 (m, 2H), 0.840-0.890 (m, 2H), −0.04 (s, 9H).

Step 4: 4-[4-Bromo-5-(4H-1,2,4-triazol-3-yl)-2-thienyl]pyridine

4-[4-Bromo-5-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,2,4-triazol-3-yl)-2-thienyl]pyridine(111.0 mg, 0.224 mmol) was dissolved in methylene chloride (3.0 mL, 47mmol). Trifluoroacetic acid (3.0 mL, 39 mmol) was added and the solutionwas stirred at rt overnight. After the reaction was completed saturatedNaHCO₃(1 mL) was added and the reaction was stirred at rt for 20 min.EtOAc (5 mL) was added, the organic layer was separated, washed withbrine, dried over MgSO₄, filtered, concentrated and the obtained residuewas purified by column chromatography (SiO₂, elution with 2-20% MeOH inDCM) to give the title compound as a yellow solid (222 mg, 54%). LCMS:(FA) ES⁺ , 307, 309. ¹H NMR (400 MHz, d₆-DMSO)) δ: 14.5 (s, br, 1H),8.70-8.72 (dd, J=1.5 Hz, 2H), 8.10 (s, 1H), 7.90-7.94 (dd, J=1.5 Hz, 2H)

Step 5:(4-Methoxyphenyl)[5-pyridin-4-yl-2-(4H-1,2,4-triazol-3-yl)-3-thienyl]methanol(Compound 85)

To a mixture of 4-[4-bromo-5-(4H-1,2,4-triazol-3-yl)-2-thienyl]pyridine(222.0 mg, 0.730 mmol) in tetrahydrofuran (5.9 mL, 72.3 mmol) cooled to−78° C. was added dropwise n-BuLi in hexanes (2.50 M, 1.2 mL, 2.90 mmol)under an atmosphere of argon and the mixture was stirred at −78° C. for30 min. To the solution was added dropwise a solution of4-methoxybenzaldehyde (0.53 mL, 4.34 mmol) in tetrahydrofuran (5.0 mL,60 mmol) and the resulting solution was stirred for 30 min at −78° C.The reaction mixture was quenched by the addition of water (2 mL) andthe resulting mixture was warmed to room temperature and stirred for 30min. The mixture was extracted with EtOAc (5 mL) then the organic layerwas separated, washed with brine, dried over MgSO₄, filtered, andconcentrated under the reduced pressure. The obtained residue waspurified by prep HPLC to yield 62.0 mg as a yellow solid (23.5%). LCMS:(FA) ES⁺ , 365. ¹H NMR (400 MHz, d₆-DMSO) δ: 8.68 (s, 1H), 8.55-8.57(dd, J=1.5 Hz, 2H), 7.81 (s, br, 1H), 7.63-7.65 (dd, J=1.5 Hz, 2H),7.40-7.44 (d, J=8.78 Hz, 2H), 6.82-6.84 (d, J=8.78 Hz, 2H), 6.72 (s, br,1H), 3.68-3.69 (s, br, 3H).

Compounds in the following table were prepared from the appropriatestarting materials in a method analogous to that of Example 7:

130 LCMS: (FA) ES+ 383.4 132 LCMS: (FA) ES+ 386.3 133 LCMS: (FA) ES+418.3 134 LCMS: (FA) ES+ 415.3 136 LCMS: (FA) ES+ 403 138 LCMS: (FA) ES+367.4 141 LCMS: (FA) ES+ 363.3 142 LCMS: (FA) ES+ 403.3 155 LCMS: (FA)ES+ 353.4 158 LCMS: (FA) ES+ 379.4 159 LCMS: (FA) ES+ 403.3 162 LCMS:(FA) ES+ 371.3 169 LCMS: (FA) ES+ 387.3 171 LCMS: (FA) ES+ 386.4 174LCMS: (FA) ES+ 363.5 175 LCMS: (FA) ES+ 386.4 183 LCMS: (FA) ES+ 381.4186 LCMS: (FA) ES+ 417, 419. 187 LCMS: (FA) ES+ 387.3 188 LCMS: (FA) ES+367.4 191 LCMS: (FA) ES+ 399.4 193 LCMS: (FA) ES+ 403.4 198 LCMS: (FA)ES+ 411. 199 LCMS: (FA) ES+ 371.4 202 LCMS: (FA) ES+ 379.4 203 LCMS:(FA) ES+ 403. 207 LCMS: (FA) ES+ 412.3 208 LCMS: (FA) ES+ 385. 214 LCMS:(FA) ES+ 412.4 215 LCMS: (FA) ES+ 393. 217 LCMS: (FA) ES+ 369.4 219LCMS: (FA) ES+ 403.4 228 LCMS: (FA) ES+ 385.4 231 LCMS: (FA) ES+ 413.3232 LCMS: (FA) ES+ 387.3 233 LCMS: (FA) ES+ 419.2 235 LCMS: (FA) ES+371.3 236 LCMS: (FA) ES+ 413.4 239 LCMS: (FA) ES+ 383.4 246 LCMS: (FA)ES+ 395.4 249 LCMS: (FA) ES+ 365.3 252 LCMS: (FA) ES+ 413.4 253 LCMS:(FA) ES+ 363.3 256 LCMS: (FA) ES+ 379.4 257 LCMS: (FA) ES+ 386.4 258LCMS: (FA) ES+ 412.3 260 LCMS: (FA) ES+ 403.2 263 LCMS: (FA) ES+ 387.3264 LCMS: (FA) ES+ 383.4 266 LCMS: (FA) ES+ 371.3 271 LCMS: (FA) ES+355.4 272 LCMS: (FA) ES+ 366.3 275 LCMS: (FA) ES+ 387.4 276 LCMS: (FA)ES+ 412.3 279 LCMS: (FA) ES+ 417, 419. 280 LCMS: (FA) ES+ 385. 281 LCMS:(FA) ES+ 403. 284 LCMS: (FA) ES+ 403

Example 8 Synthesis of4-[4-(4-chlorobenzyl)-5-(4H-1,2,4-triazol-3-yl)-2-thienyl]pyridine(Compound 5)

Step 1:4-[4-(4-Chlorobenzyl)-5-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,2,4-triazol-3-yl)-2-thienyl]pyridine

Bis(tri-t-butylphosphine)palladium(0) (4.38 mg, 0.00857 mmol) and4-[4-bromo-5-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,2,4-triazol-3-yl)-2-thienyl]pyridine(0.075 g, 0.17 mmol) were combined in a dry round bottomed flask fittedwith a stirbar and sealed with a septum. The flask wasevacuated/refilled with nitrogen three times then a solution of4-chlorobenzylzinc chloride in tetrahydrofuran (0.50M, 0.720 mL, 0.360mmol) was added dropwise via a syringe. A nitrogen line was attached andthe reaction was stirred at rt for 30 minutes, then at 60° C. for 2hours. The reaction was cooled to rt, diluted with EtOAc and saturatedammonium chloride solution, then the mixture was transferred to aseparatory funnel. The organic layer was separated and the aqueous layerwas extracted twice more with EtOAc. The organics were combined, washedwith bicarbonate solution, then brine, then dried over sodium sulfate.The mixture was filtered then evaporated in vacuo and the residue waspurified by column chromatography on silica, elution 100% hexane to 100%EtOAc to afford the title compound as a light yellow oil. Yield 63 mg(76% yield). LCMS: (FA) ES+, 483, 485.

Step 2:4-[4-(4-Chlorobenzyl)-5-(4H-1,2,4-triazol-3-yl)-2-thienyl]pyridine(Compound 5)

The4-[4-(4-chlorobenzyl)-5-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,2,4-triazol-3-yl)-2-thienyl]pyridine(58 mg, 0.12 mmol) and methylene chloride (4.0 mL, 62 mmol) werecombined in a round bottomed flask equipped with a stirbar. The mixturewas stirred and trifluoroacetic acid (1.1 mL, 14 mmol) was added in oneportion. The resulting yellow solution was stirred overnight at rt underan atmosphere of nitrogen. Excess solvent was removed on the rotovap andthe residue was digested in a mixture of EtOAc and aqueous sodiumbicarbonate solution. The mixture was stirred then transferred to aseparatory funnel. The organic layer was separated and the aqueous layerwas extracted twice more with EtOAc. The organics were combined, washedwith bicarbonate solution, then saline, and then dried over sodiumsulfate. The mixture was filtered then evaporated in vacuo and theresidue was purified by column chromatography on silica, elution 100%DCM to 100% EtOAc to afford the title compound as an off-white powder.Yield 41 mg (97% yield). LCMS: (FA) ES+, 353, 355. ¹H NMR (400 MHz,d₆-DMSO) δ: 14.31 (1H, br s), 8.67 (1H, br s), 8.55 (2H, d, J=6.3 Hz),7.69 (1H, s), 7.63 (2H, d, J=6.3 Hz), 7.36-7.30 (4H, m), 4.47 (2H, s).

Compounds in the following table were prepared from the appropriatestarting materials in a method analogous to that of Example 8:

87 LCMS: (FA) ES+ 370.

Example 9 Synthesis of6-chloro-2-methyl-1-[2-(1H-pyrazol-5-yl)-5-pyridin-4-yl-3-thienyl]-1,2,3,4-tetrahydroisoquinoline(Compound 58)

Step 1: 2,5-Dibromo-3-thenoic Acid

In a 500 mL round bottomed flask was placed 3-thenoic acid (16.04 g,125.2 mmol) and acetic acid (200 mL, 4000 mmol). To the mixture wasadded bromine (32.24 mL, 625.8 mmol) and the mixture was stirred for 18h at 60° C. The mixture was allowed to cool to rt then was diluted withice-water. Sodium bisulfite (52.10 g, 500.7 mmol) was added. Theresulting precipitate was collected by filtration and then washed withwater to give 5-dibromo-3-thenoic acid as an off-white powder (33.4,93.3%). LCMS (FA) ES+ 284.9, 286.9.

Step 2: 2,5-dibromo-N-[2-(3-chlorophenyl)ethyl]thiophene-3-carboxamide

To a mixture of 2,5-dibromo-3-thenoic Acid (10.0 g, 35.0 mmol),2-(3-chlorophenyl)ethanamine (7.08 g, 45.5 mmol) and1-hydroxybenzotriazole hydrate (5.89 g, 38.5 mmol) in methylene chloride(291 mL, 4550 mmol) was addedN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (12.1 g,62.9 mmol). The mixture was stirred at rt overnight. The reactionmixture was washed with 1NHCl, water, saturated sodium bicarbonate andbrine. The DCM layer was dried and evaporated to afford5-dibromo-N-[2-(3-chlorophenyl)ethyl]thiophene-3-carboxamide (14.7,99.2%). LCMS (FA) ES+ 423.9, 425.9.

Step 3: 6-chloro-1-(2,5-dibromo-3-thienyl)-3,4-dihydroisoquinoline

To a mixture of2,5-dibromo-N-[2-(3-chlorophenyl)ethyl]thiophene-3-carboxamide (5.15 g,12.2 mmol) in xylenes (25.98 mL, 70.32 mmol) at 70° C. was addedphosphorus pentoxide (13.0 g, 45.8 mmol) and then phosphoryl chloride(12.0 mL, 129 mmol). The mixture was heated at 150° C. for 60 h, thenthe mixture was cooled to rt. The solution was removed by decantationand washed with toluene twice. Water (20 mL) and 20% NaOH (20 mL) wereadded and the mixture was sonicated. The mixture was extracted withEtOAc. The organic layer was washed with water, dried over MgSO4, andevaporated in vacuo to give a residue which was purified bychromatography to afford6-chloro-1-(2,5-dibromo-3-thienyl)-3,4-dihydroisoquinoline as foam solid(2.8 g, 57%).

Step 4: tert-Butyl6-chloro-1-(2,5-dibromo-3-thienyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate

To a mixture of6-chloro-1-(2,5-dibromo-3-thienyl)-3,4-dihydroisoquinoline (2.60 g, 6.41mmol) in ethanol (37.43 mL, 641.1 mmol) was addeddi-tert-butyldicarbonate (2.80 g, 12.8 mmol) and sodium tetrahydroborate(0.485 g, 12.8 mmol) at 0° C. The mixture was stirred for 20 min at 0°C. and then overnight at rt. The reaction mixture was concentrated andthe residue was extracted with EtOAc. The organic layer was separated,washed with water, washed with brine, and then dried over MgSO4. Thesolvent was evaporated and the residue was purified by chromatography toafford tert-butyl6-chloro-1-(2,5-dibromo-3-thienyl)-3,4-dihydroisoquinoline-2(1H)—carboxylate as a white powder (2.45 g, 75.3%).

Step 5: tert-Butyl1-(2-bromo-5-pyridin-4-yl-3-thienyl)-6-chloro-3,4-dihydroisoquinoline-2(1H)-carboxylate

A mixture of tert-butyl6-chloro-1-(2,5-dibromo-3-thienyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(177.0 mg, 0.3486 mmol), pyridine-4-boronic acid (51.43 mg, 0.4184 mmol)tetrakis(triphenylphosphine)palladium(0) (20.1 mg, 0.0174 mmol) andcesium carbonate (0.341 g, 1.04 mmol) in 1,4-dioxane (6.0 mL, 77 mmol)and water (2.0 mL, 110 mmol) was degassed and heated at 100° C. for 1 h.The mixture was extracted with EtOAc. The organic layer was separatedand washed with water. The organic layer was dried and evaporated toleave a residue which was purified by chromatography to affordtert-butyl1-(2-bromo-5-pyridin-4-yl-3-thienyl)-6-chloro-3,4-dihydroisoquinoline-2(1H)-carboxylateas a white solid (72 mg, 41%). LCMS AA ES+ 505.1, 507.1

Step 6: tert-Butyl6-chloro-1-[2-(1H-pyrazol-5-yl)-5-pyridin-4-yl-3-thienyl]-3,4-dihydroisoquinoline-2(1H)-carboxylate

A mixture of tert-butyl1-(2-bromo-5-pyridin-4-yl-3-thienyl)-6-chloro-3,4-dihydroisoquinoline-2(1H)-carboxylate(72.0 mg, 0.142 mmol),3-(4,4,5,5-tetramethyl-1,3,2-dioxabolone)-pyrrazole (27.6 mg, 0.142mmol), [1,1′-bis(diphenylphosphino)ferrocene]palladium(II)dichloride(11.7 mg, 0.0142 mmol) and sodium carbonate (29 mg, 0.27 mmol) in1,2-dimethoxyethane (3.0 mL, 29 mmol) and water (1.0 mL, 56 mmol) washeated at 95° C. for 4.5 h. A LCMS showed the desired product togetherwith unreacted starting material. Additional[1,1′-bis(diphenylphosphino)ferrocene]palladium(II)dichloride (11.7 mg,0.0142 mmol) 3-(4,4,5,5-Tetramethyl-1,3,2-dioxabolone)-pyrrazole (56 mg,0.29 mmol), tetrakis(triphenylphosphine)palladium(0) (15 mg, 0.013mmol), sodium carbonate (100 mg, 0.9 mmol) and 1,2-dimethoxyethane (3.0mL, 29 mmol) were added. The mixture was heated at 100° C. for another 4h. The mixture was dry-loaded onto silica gel and purified bychromatography to afford tert-butyl6-chloro-1-[2-(1H-pyrazol-5-yl)-5-pyridin-4-yl-3-thienyl]-3,4-dihydroisoquinoline-2(1H)-carboxylate(41 mg, 58%). LCMS AA ES+ 493.2, 495.1.

Step 7:6-Chloro-2-methyl-1-[2-(1H-pyrazol-5-yl)-5-pyridin-4-yl-3-thienyl]-1,2,3,4-tetrahydroisoquinoline(Compound 58)

To a solution of tert-butyl6-chloro-1-[2-(1H-pyrazol-5-yl)-5-pyridin-4-yl-3-thienyl]-3,4-dihydroisoquinoline-2(1H)-carboxylate(41 mg, 0.083 mmol) in tetrahydrofuran (3.0 mL, 37 mmol) was addedlithium tetrahydroaluminate (0.249 mmol, 0.249 mmol) in THF (2.0 mM) at−78° C. After the addition, the temperature of the reaction was raisedto rt for 30 min and then heated at 85° C. for 5 h. The mixture wasquenched with water, diluted with methanol, and extracted with ethylacetate. The organic phase was dried, filtered and evaporated. Theresidue was loaded onto silica gel and purified by chromatography toafford6-chloro-2-methyl-1-[2-(1H-pyrazol-5-yl)-5-pyridin-4-yl-3-thienyl]-1,2,3,4-tetrahydroisoquinoline(5.1 mg, 15%). LCMS AA ES+ 407.2, 409.1; ¹H NMR (400 MHz, d₄-methanol)δ: 8.48 (d, J=5.06 Hz, 2H), 7.89-7.66 (m, 1H), 7.61 (s, 2H), 7.50-7.31(br, 1H), 7.17 (s, 1H), 7.00 (d, J=7.98 Hz, 1H), 6.87-6.48 (m, 2H),5.16-4.94 (m, 1H), 3.34 (s, 1H), 3.28-3.10 (m, 2H), 2.94-2.79 (m, 1H),2.72-2.56 (m, 1H), 2.26 (s, 3H)

Example 10 Synthesis of4-(4-chlorobenzyl)-2-(pyridin-4-yl)-5-(4H-1,2,4-triazol-3-yl)thiazole(Compound 76)

Step 1: Ethyl 4-(4-chlorophenyl)-3-oxobutanoate

To a suspension of potassium ethyl malonate (17.12 g, 100.6 mmol) inacetonitrile (150 mL) were added N,N-diisopropylethylamine (28 mL, 160mmol) and magnesium chloride (12.11 g, 127.2 mmol). The resultingmixture was stirred for 1 hour. A solution of 4-chlorophenylacetylchloride (10.12 g, 53.53 mmol) in acetonitrile (100 mL) was then addedand the mixture was heated to 60° C. and stirred for 20 hours. Themixture was cooled to room temperature and concentrated under reducedpressure. The residue was suspended in 1N aqueous HCl (250 mL) and wasextracted with EtOAc (100 mL×2). The combined organic phases were driedover anhydrous MgSO4 and insoluble materials were removed by filtration.The filtrate was concentrated under reduced pressure and the residue waspurified by column chromatography on silica, elution with a 0%-80%mixture of EtOAc in hexane (linear gradient, 45 min) to obtain ethyl4-(4-chlorophenyl)-3-oxobutanoate (5.0 g, 39%) as a yellow oil. LCMS(FA) ES− 239. ¹H NMR (d₆-DMSO, 400 MHz): δ: 7.37 (2H, d, J=13.8 Hz),7.20 (2H, d, J=13.8 Hz), 4.07 (2H, q, J=7.2 Hz), 3.89 (2H, s), 3.66 (2H,s), 1.17 (3H, t, J=7.2 Hz).

Step 2: Ethyl 2-bromo-4-(4-chlorophenyl)-3-oxobutanoate

In a 250 mL round bottomed flask were placed ethyl4-(4-chlorophenyl)-3-oxobutanoate (4.04 g, 16.8 mmol) and methylenechloride (100 mL). To the solution was added N-bromosuccinimide (3.13 g,17.6 mmol) and the mixture was stirred for 3 h at rt. To the mixture wasadded a freshly prepared 10% aqueous solution of NaHSO3 (5 g NaHSO₃dissolved in 50 mL water) and the resulting biphasic mixture wasvigorously stirred for 15 min at rt. The organic phase was separated andthe aqueous phase was extracted with DCM (30 mL). The organic phaseswere combined and washed with a saturated aqueous solution of NaHCO₃ (50mL) and dried over anhydrous MgSO₄. Insoluble materials were removed byfiltration and the filtrate was concentrated under reduced pressure. Theresidual yellow oil was essentially pure and was used in the next stepwithout further purification. LCMS (FA) ES− 319.

Step 3: Ethyl 2-amino-4-(4-chlorobenzyl)thiazole-5-carboxylate

In a 100 mL round bottomed flask were placed ethyl2-bromo-4-(4-chlorophenyl)-3-oxobutanoate (990 mg, 3.1 mmol) andisopropyl alcohol (20 mL). To the mixture was added thiourea (590 mg,7.8 mmol) and the reaction was then refluxed for 16 h with stirring. Themixture was allowed to cool to rt and was then concentrated underreduced pressure. The residue was suspended in EtOAc (50 mL) and thenwashed with a saturated aqueous solution of NaHCO₃ (50 mL), brine (50mL), and dried over anhydrous MgSO4. Insoluble materials were removed byfiltration and the filtrate was concentrated under reduced pressure. Theresidual off-white yellowish crystalline solid was essentially pure byLCMS and was used in the next step without further purification. LCMS(FA) ES+ 296. ¹H NMR (d₆-DMSO, 400 MHz): δ: 7.80 (2H, br s), 7.32 (2H,d, J=8.8 Hz), 7.23 (2H, d, J=8.8 Hz), 4.14-4.20 (4H, m), 1.22 (3H, t,J=7.1 Hz).

Step 4: Ethyl 2-bromo-4-(4-chlorobenzyl)thiazole-5-carboxylate

In a 250 mL round bottomed flask were placed ethyl2-amino-4-(4-chlorobenzyl)-1,3-thiazole-5-carboxylate (786 mg, 2.65mmol) and acetonitrile (75 mL). To the mixture was added copper (II)bromide (963 mg, 4.31 mmol). The suspension was stirred for 15 min atrt. To the mixture was added tert-butyl nitrite (0.630 mL, 5.30 mmol)and the stirring was continued for an additional 1.5 h at 70° C. Thereaction mixture was allowed to cool to rt and was then concentratedunder reduced pressure. The residue was purified by columnchromatography on silica, elution with a 10%-50% mixture of EtOAc inhexane to obtain ethyl2-bromo-4-(4-chlorobenzyl)-1,3-thiazole-5-carboxylate (820 mg; 86%) asan yellow syrup, which spontaneously solidified on standing at rt toafford off-white crystalline solid. LCMS (FA) ES+ 362. ¹H NMR (CDCl3,400 MHz): δ: 7.29 (2H, d, J=8.8 Hz), 7.24 (2H, d, J=8.8 Hz), 4.44 (2H,s), 4.35 (2H, q, J=7.3 Hz), 1.36 (3H, t, J=7.3 Hz).

Step 5: Ethyl 2-bromo-4-(4-chlorobenzyl)thiazole-5-carboxylic acid

In a 100 mL round bottomed flask were placed ethyl2-bromo-4-(4-chlorobenzyl)-1,3-thiazole-5-carboxylate (955 mg, 2.65mmol) and tetrahydrofuran (50 mL, 600 mmol). To this solution was addeda freshly prepared aqueous solution of lithium hydroxide [(lithiumhydroxide.H₂O (177 mg, 4.22 mmol) and water (15 mL, 830 mmol)). Themixture was stirred for 4 h at rt then MeOH (20 mL) was added and themixture was refluxed for 3 h. The mixture was allowed to cool to rt andthen acidified by the addition of 1.0N HCl aq (4.5 mL). The mixture wasstirred for 1 h at rt. The mixture was then concentrated under reducedpressure until reduced to ca 5 mL volume. EtOAc (50 mL) was added andthe mixture was washed with water (50 mL), then brine (50 mL), then wasdried over anhydrous MgSO4. Insoluble materials were removed byfiltration and the filtrate was concentrated under reduced pressure. Theresidual yellow crystalline solid was used in the next step withoutfurther purification. LCMS (FA) ES+ 332.

Steps 6 and 7: 2-Bromo-4-(4-chlorobenzyl)thiazole-5-carboxamide

In a 250 mL round bottomed flask were placed2-bromo-4-(4-chlorobenzyl)-1,3-thiazole-5-carboxylic acid (800 mg, 2mmol) and toluene (30 mL, 300 mmol). To the suspension was added thionylchloride (700 uL, 10 mmol) and the mixture was refluxed for 2 h duringwhich time the suspension turned into a solution. The reaction wasallowed to cool to rt and then was concentrated under reduced pressure.The residue was co-evaporated with toluene (10 mL). The residual orangeoil was dissolved in methylene chloride (30 mL, 500 mmol) thenN,N-dimethylaminopyridine (21.2 mg, 0.174) was added. To the mixture wasadded ammonium hydroxide in water (8.5 M, 20 mL) and the mixture wasstirred for 1.5 h at rt. The organic phase was separated and the aqueousphase was extracted with DCM (30 mL). The organic phase and extract werecombined and dried over anhydrous MgSO4. Insoluble materials wereremoved by filtration and the filtrate was concentrated under reducedpressure. The residual yellow syrup was used in the next step withoutfurther purification. LCMS (FA) ES+ 333.

Step 8:(Z)-2-bromo-4-(4-chlorobenzyl)-N-((dimethylamino)methylene)thiazole-5-carboxamide

In a 250 mL round bottomed flask were placed2-bromo-4-(4-chlorobenzyl)-1,3-thiazole-5-carboxamide (0.66 g, 2.0 mmol)and toluene (30 mL, 300 mmol). The mixture was turned into a suspensionby ultrasonication. To the suspension was added1,1-dimethoxy-N,N-dimethylmethanamine (80 uL, 6.0 mmol) and the mixturewas stirred for 2 h at 50° C. The mixture was allowed to cool to rt thenwas concentrated under reduced pressure. The residue was used in thenext step without further purification. LCMS (FA) ES+ 388.

Step 9: 2-Bromo-4-(4-chlorobenzyl)-5-(4H-1,2,4-triazol-3-yl)thiazole

In a 250 mL round bottomed flask were placed2-bromo-4-(4-chlorobenzyl)-N-[(1Z)-(dimethylamino)methylene]-1,3-thiazole-5-carboxamideand acetic acid (50 mL, 900 mmol). Hydrazine hydrate (490 uL, 10 mmol)was added and the mixture was stirred for 1 h at 50° C. The mixture wasallowed to cool to rt, then was concentrated under reduced pressure toobtain 3-[2-bromo-4-(4-chlorobenzyl)-1,3-thiazol-5-yl]-4H-1,2,4-triazoleas a yellowish off-white crystalline solid. The crude material was usedin the next step without further purification. LCMS (FA) ES+ 357.

Step 10:2-Bromo-4-(4-chlorobenzyl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl)thiazole

In a 250 mL round bottomed flask were placed3-[2-bromo-4-(4-chlorobenzyl)-1,3-thiazol-5-yl]-4H-1,2,4-triazole (0.7g, 2 mmol) and tetrahydrofuran (50 mL, 600 mmol). To the mixture wereadded dihydropyran (2 mL, 20 mmol) and p-toluenesulfonic acidmonohydrate (911.3 mg, 4.791 mmol). The mixture was refluxed for 2 hthen was allowed to cool to rt and then a saturated aqueous solution ofNaHCO₃ (50 mL) was added. The resulting biphasic mixture was vigorouslystirred for 30 min at rt. The aqueous phase was separated then wasextracted with EtOAc (50 mL×2). The combined organic phases were driedover anhydrous MgSO₄. Insoluble materials were removed by filtration andthe filtrate was concentrated under reduced pressure. The residue waspurified by column chromatography on silica, elution with a 10%-80%mixture of EtOAc in hexane (linear gradient, 30 min) to afford3-[2-bromo-4-(4-chlorobenzyl)-1,3-thiazol-5-yl]-1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazole(778 mg; 67% six steps) as a yellow syrup which spontaneously solidifiedon standing at rt for 2 days. LCMS (FA) ES+ 441. ¹H NMR (d₆-DMSO, 400MHz): δ: 8.89 (1H, s), 7.28-7.34 (4H, m), 5.62 (1H, dd, J=2.8 and 9.6Hz), 4.52 (2H, s), 3.92-3.96 (1H, m), 3.63-3.70 (1H, m), 1.91-2.14 (3H,m), 1.52-1.72 (3H, m)

Step 11:4-(4-Chlorobenzyl)-2-(pyridin-4-yl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl)thiazole

To a 20 mL vial was added a solution of3-[2-bromo-4-(4-chlorobenzyl)-1,3-thiazol-5-yl]-1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazole(0.1500 g, 0.3411 mmol) and 4-(tributylstannyl)pyridine (0.2511 g,0.6822 mmol) in anhydrous 1,4-dioxane (5.000 mL). The solution wasdegassed for 10 minutes. Lithium chloride (0.108 g, 2.56 mmol) andcopper (I) iodide (0.0487 g, 0.256 mmol) were added followed bytetrakis(triphenylphosphine)palladium(0) (0.0492 g, 0.0426 mmol). Thereaction mixture was heated to 90° C. and allowed to stir for 18 h. Thereaction was cooled to ambient temperature and quenched by the additionof a saturated aqueous solution of sodium bicarbonate (10 mL). Thequench mixture was extracted with EtOAc (10 mL×3). The combined organiclayers were dried over anhydrous Na₂SO₄, filtered and concentrated underreduced pressure. The crude material was purified by columnchromatography on silica (gradient DCM to 10% MeOH over 30 min) toafford the product (0.2245 g, 73%) as a yellow solid. LCMS (AA) ES+ 438.¹H NMR (400 MHz, d₆-DMSO) δ: 8.92 (s, 1H), 7.90 (d, J=4.8 Hz, 2H), 7.65(d, J=1.2 Hz, 2H), 7.38-7.32 (m, 4H), 5.66 (dd, J=9.6, 2.8 Hz, 1H), 4.65(s, 2H), 3.97-3.94 (m, 1H), 3.72-3.66 (m, 1H), 1.59-1.48 (m, 2H),1.32-1.23 (m, 2H), 1.10-1.06 (m, 2H).

Step 12:4-(4-Chlorobenzyl)-2-(pyridin-4-yl)-5-(4H-1,2,4-triazol-3-yl)thiazole(Compound 76)

To a 20 mL vial was added a solution of4-{4-(4-chlorobenzyl)-5-[1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl]-1,3-thiazol-2-yl}pyridine(0.2245 g, 0.635 mmol) in anhydrous tetrahydrofuran (2.000 mL) andmethanol (2.000 mL). 4.0 M Hydrochloric acid in 1,4-dioxane (1.0 mL, 4.0mmol) was added and the reaction mixture was allowed to stir at 50° C.for 18 hours. The reaction was cooled to ambient temperature andquenched by the addition of a saturated aqueous solution of sodiumbicarbonate (10 mL) and extracted with EtOAc (10 mL×3). The combinedorganic phases were dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure. The crude material was purified byHPLC to afford the product (0.0423 g, 45%) as an off white solid. LCMS(AA) ES+ 354. ¹H NMR (400 MHz, d₆-DMSO) δ: 14.48 (s, 1H), 8.71 (dd,J=4.4, 1.2 Hz, 2H), 7.89-7.87 (m, 2H), 7.38-7.32 (m, 4H), 4.67 (s, 2H).

Compounds in the following table were prepared from the appropriatestarting materials in a method analogous to that of Example 10:

37 LCMS: (FA) ES+ 372, 374. 39 LCMS: (AA) ES+ 355, 357. 46 LCMS: (AA)ES− 370, 372. 63 LCMS: (FA) ES+ 383, 385. 78 LCMS: (AA) ES+ 372, 374.

Example 11 Synthesis of4-(4-Chlorobenzyl)-2-(2-methylpyridin-4-yl)-5-(4H-1,2,4-triazol-3-yl)thiazole(Compound 18)

Step 1:4-(4-chlorobenzyl)-2-(2-methylpyridin-4-yl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl)thiazole

To a 20 mL vial was added a solution of3-[2-bromo-4-(4-chlorobenzyl)-1,3-thiazol-5-yl]-1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazole(0.1000 g, 0.2274 mmol) and2-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)pyridine(0.0931 g, 0.425 mmol) in a solution of 1,4-dioxane (2.5000 mL, 32.036mmol) and water (0.2500 mL). Cesium carbonate (0.2223 g, 0.6822 mmol)was added followed by tetrakis(triphenylphosphine)palladium(0) (0.031533g, 0.027288 mmol). The reaction mixture was heated to 90° C. and allowedto stir for 18 h. The reaction was cooled to ambient temperature andquenched by the addition of a saturated aqueous solution of sodiumbicarbonate (10 mL) and extracted with EtOAc (10 mL×3). The combinedorganic phases were dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure. The crude material was dry loadedonto silica gel then was purified by column chromatography on silica(gradient DCM to 10% MeOH over 30 min) to afford the product with Ph₃POimpurities (0.1654 g, 96.6%) as a brown oil. LCMS (AA) ES+ 452. ¹H NMR(400 MHz, d₆-DMSO) δ: 8.91 (s, 1H), 7.64-7.53 (m, 3H), 7.37-7.31 (m,4H), 5.66 (dd, J=9.6, 2.8 Hz, 1H), 4.61 (s, 2H), 3.72-3.66 (m, 2H), 2.55(s, 3H), 1.70-1.68 (m, 2H), 1.62-1.48 (m, 2H), 1.45-1.38 (m, 2H).

Step 2:4-(4-Chlorobenzyl)-2-(2-methylpyridin-4-yl)-5-(4H-1,2,4-triazol-3-yl)thiazole(Compound 18)

To a 20 mL vial was added a solution of4-{4-(4-chlorobenzyl)-5-[1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl]-1,3-thiazol-2-yl}-2-methylpyridine(0.1654 g, 0.365 mmol) in anhydrous tetrahydrofuran (2.000 mL) andmethanol (2.000 mL). 4.0 M hydrochloric acid in 1,4-dioxane (1.0 mL, 4.0mmol) was added and the reaction mixture was allowed to stir at 50° C.for 18 hours. The reaction was cooled to ambient temperature andquenched by the addition of a saturated aqueous solution of sodiumbicarbonate (10 mL) then was extracted with EtOAc (10 mL×3). Thecombined organic layers were dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure. The crude material was purified byHPLC to afford the product (0.0351 g, 39.9%) as a white solid. LCMS (AA)ES+ 368, 370. ¹H NMR (400 MHz, d₆-DMSO) δ: 8.73 (s, 1H), 8.56 (d, J=5.2Hz, 1H), 7.75 (s, 1H), 7.67 (dd, J=5.2, 1.6 Hz, 1H), 7.37-7.32 (m, 4H),4.65 (s, 2H) 2.55 (s, 3H).

Compounds in the following table were prepared from the appropriatestarting materials in a method analogous to that of Example 11:

137 LCMS: (FA) ES+ 354, 356. 213 LCMS: (FA) ES+ 427.

Example 12 Synthesis of4-(4-chlorobenzyl)-2-(pyridin-4-yl)thiazole-5-carboxylic acid (Compound80)

Step 1:5-(2-(4-Chlorophenyl)-1-hydroxyethylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione

To a mixture of 2,2-dimethyl-1,3-dioxane-4,6-dione (52.7 g, 366 mmol) inDCM (205 mL) at −10° C. in an ice/methanol bath was added pyridine (72.5mL, 897 mmol) over 10 minutes. To the resulting solution at −10° C. wasadded a solution of 2-(4-chlorophenyl)acetyl chloride (69.1 g, 366 mmol)in DCM (144 mL) dropwise over 1 hour. The mixture was stirred at −10° C.for 1 hour, then at room temperature for 1 hour. The mixture was pouredinto a mixture of 2 M HCl (820 mL) and ice (400 mL) and the aqueouslayer was extracted with DCM (2×200 mL). The combined DCM layers werewashed with 1 N HCl (100 mL) and brine (100 mL). The combined organiclayers were dried over MgSO₄, filtered, and concentrated in vacuo togive 103 g of title compound. (95% yield). LC/MS (FA) ES− 295. ¹H NMR(400 MHz, CDCl₃) δ: 15.25 (br s, 1H), 7.34-7.26 (m, 4H), 4.37 (s, 2H),1.72 (s, 6H).

Step 2: Ethyl 4-(4-chlorophenyl)-3-oxobutanoate

A solution of5-(2-(4-chlorophenyl)-1-hydroxyethylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione(103 g, 347 mmol) in ethanol (718 mL) was refluxed for 3 hours. Thereaction was cooled and concentrated in vacuo. The residue was purifiedby silica gel chromatography (ethyl acetate/hexane=0/100→20/80) to give61 g of the title compound as an orange oil. (73% yield). LC/MS (FA) ES+241. ¹H NMR (400 MHz, CDCl₃) δ: 7.32-7.28 (m, 2H), 7.15-7.11 (m, 2H),4.17 (q, 2H, J=7.2 Hz), 3.81 (s, 2H), 3.45 (s, 2H), 1.26 (t, 3H, J=7.2Hz).

Step 3: Ethyl 2-chloro-4-(4-chlorophenyl)-3-oxobutanoate

To a solution of ethyl 4-(4-chlorophenyl)-3-oxobutanoate (61.0 g, 253mmol) in DCM (811 mL) in an ice bath was added sulfuryl chloride (34.2g, 253 mmol) and the resulting solution was allowed to stir at roomtemperature overnight. The reaction was quenched with saturated sodiumbicarbonate solution (200 mL) and the layers separated. The organiclayer was washed with brine (100 mL), dried over MgSO₄, filtered, andconcentrated in vacuo to give 70.8 g of title compound. (100% yield). ¹HNMR (400 MHz, CDCl₃) δ: 7.33-7.30 (m, 2H), 7.17-7.14 (m, 2H), 4.85 (s,1H), 4.26 (dq, 1H, J=7.2, 1.2 Hz), 4.02 (d, 1H, J=16.8 Hz), 3.97 (d,J=16.8 Hz, 1H), 1.29 (t, 3H, J=7.2 Hz).

Step 4: Ethyl 4-(4-chlorobenzyl)-2-(pyridin-4-yl)thiazole-5-carboxylate

To a solution of ethyl 2-chloro-4-(4-chlorophenyl)-3-oxobutanoate (70.8g, 257 mmol) in IPA (2.96 L) was added thioisonicotinamide (71.1 g, 515mmol) and the resulting mixture was refluxed for 3 days. The reactionwas cooled and concentrated in vacuo and the residue was partitionedbetween DCM (300 ml) and saturated sodium bicarbonate solution (200 mL).The layers were separated and the aqueous layer was extracted with DCM(100 mL). The combined DCM layers were washed with brine (100 mL), driedover MgSO₄, filtered, and concentrated in vacuo to give crude productwhich was purified by silica gel chromatography (ethylacetate/DCM=0/100→40/60) followed by recrystallization from ethylacetate/hexanes to give 33 g of the title compound as yellow crystals.(36% yield). LCMS (FA) ES+ 359. ¹H NMR (400 MHz, CDCl₃) δ: 8.74-8.72 (m,2H), 7.81-7.80 (m, 2H), 7.36-7.32 (m, 2H), 7.27-7.23 (m, 2H), 4.54 (s,2H), 4.38 (q, 2H, J=7.2 Hz), 1.40 (t, 3H, J=7.2 Hz).

Step 5: 4-(4-chlorobenzyl)-2-(pyridin-4-yl)thiazole-5-carboxylic acid(Compound 80)

To a solution of ethyl4-(4-chlorobenzyl)-2-(pyridin-4-yl)thiazole-5-carboxylate (12.8 g, 35.7mmol) in THF (200 mL) and water (100 mL) was added 1.0 M LiOH (46.4 mL,46.4 mmol) and the resulting solution was stirred at room temperatureovernight. The mixture was acidified to pH 4 with 1 N HCl. Theprecipitated solids were filtered, washed with water and dried to give11 g of the title compound as an a white solid. (93% yield). LCMS (FA)ES+ 331. ¹H NMR (400 MHz, d₆-DMSO) δ: 13.86 (br s, 1H), 8.72-8.71 (m,2H), 7.89-7.87 (m, 2H), 7.36-7.29 (m, 4H), 4.50 (s, 2H).

Example 13 Synthesis ofN-{4-[4-(4-chlorobenzyl)-5-(4H-1,2,4-triazol-3-yl)-1,3-thiazol-2-yl]pyridin-2-yl}acetamide(Compound 56)

Step 1: 2,4-Dibromo-1,3-thiazole-5-carboxylic acid

To a 500 mL 3-neck round bottom flask equipped with dropping funnel andinternal temperature monitor was added THF (200 mL) andN,N-diisopropylamine (14.7 mL, 105 mmol) under atmosphere of argon.After cooling at −75° C., 2.50 M of n-Butyllithium in hexane (41.1 mL,103 mmol) was added dropwise into the solution over 30 min. The internaltemperature was kept below −70° C. and the resulting solution wasstirred for 15 min at −75° C. To this LDA solution was added a solutionof 2,4-dibromothiazole (25.0 g, 99.8 mmol) in THF (60 mL) via droppingfunnel over 40 min and the internal temperature was kept below −70° C.,then this solution was stirred for 20 min at −75° C. To this solutionwas added crushed dry ice at −75° C. and the mixture was stirred for 15min. At that time, 10 mL water was added dropwise. The cooling bath wasremoved and the mixture was brought to rt over 1 h with a water bath.The solvent was evaporated under reduced pressure to give a solidresidue. The residue was suspended in 100 mL water, basified with 1.00 Mof sodium hydroxide in water (110 mL) and extracted with 100 mL ether.The ether layer was washed with 0.5 N NaOH (2×30 mL). The combinedaqueous solution was acidified with conc. HCl to ˜pH 2, extracted withether (5×100 mL, adjusting the pH to ˜2 each time after separation). Thecombined ether solutions were washed with brine, dried over Na₂SO₄,filtered, evaporated to give a solid product (28.04 g, 98%). LCMS: (FA)ES+ 288, ES− 286.

Step 2: 2,4-Dibromo-1,3-thiazole-5-carboxamide

A suspension of 2,4-dibromo-1,3-thiazole-5-carboxylic acid (16.33 g,56.91 mmol) in dry DCM (250 mL) and DMF (0.400 mL) was cooled in an icebath. Thionyl chloride (40.0 mL, 548 mmol) was added dropwise. Thecooling bath was removed and the suspension was stirred at rt for 2.5hours. Toluene (80 mL, 800 mmol) was added and the suspension was heatedto reflux for 1 hour. The mixture was cooled to room temperature, thesolvent was removed and the residue was azeotroped with toluene (2×100mL) to give a crude intermediate. This material was suspended in DCM(230 mL) and cooled in an ice bath. N,N-Dimethylaminopyridine (0.70 g,5.7 mmol) was added, followed by the slow addition of 8.5 M ammoniumhydroxide in water (100.0 mL, 850.0 mmol). The mixture was stirred atroom temperature overnight. The mixture was filtered and the aqueouslayer was separated and extracted with DCM (3×100 mL). The combined DCMlayers were washed with water, brine, dried over Na₂SO₄, filtered, andevaporated to give a solid product (11.2 g, 69%). LCMS: (FA) ES+ 287 andES− 285.

Step 3: 3-(2,4-Dibromo-1,3-thiazol-5-yl)-4H-1,2,4-triazole

To a suspension of 2,4-dibromo-1,3-thiazole-5-carboxamide (0.110 g,0.385 mmol) in dry toluene (8.0 mL, 75 mmol) was added DMF-DMA (0.204mL, 1.54 mmol). The mixture was stirred at 60° C. under a nitrogenatmosphere for 3 hours. The solvent was removed and to the intermediatewas added acetic acid (2.0 mL, 35 mmol), followed by hydrazine (0.0604mL, 1.92 mmol). The mixture was heated to 120° C. for 30 min. Themixture was cooled to room temperature, the solvent was removed and theresidual acetic acid was azeotroped with toluene (2×5 mL) to give anoily material, which was basified with saturated aqueous NaHCO3 to pH˜8and extracted with EtOAc (3×30 mL). The EtOAc layer was washed withwater, brine, dried over Na₂SO₄, filtered, and evaporated to give acrude product. Chromatography on a silica column using EtOAc/hexane(0/100 to 50/50) gave a solid product (0.073 g, 61%). LCMS: (FA) ES+ 311and ES− 309. ¹H NMR (400 MHz, d₄-methanol) δ: 8.53 (s, 1H).

Step 4:3-(2,4-Dbromo-1,3-thiazol-5-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,2,4-triazole

To the solution of 3-(2,4-dibromo-1,3-thiazol-5-yl)-4H-1,2,4-triazole(1.16 g, 3.74 mmol) in dry DMF (5.0 mL) at 0° C. was added portionwisesodium hydride (60%, 0.180 g, 4.49 mmol). The ice bath was removed,mixture was stirred for 5 min at ambient temperature then cooled in anice bath. [β-(Trimethylsilyl)ethoxy]methyl chloride (0.795 mL, 4.49mmol) in dry DMF (2.0 mL) was added dropwise and the mixture was stirredat room temperature for 2 hours. The mixture was quenched withice-water, extracted with EtOAc, washed with brine, dried over Na₂SO₄,filtered, evaporated to give a crude oil. The product was purified bycolumn chromatography on silica gel, eluting with EtOAc/hexane (0/100 to20/80) to afford a white solid product (1.10 g, 67%). LCMS: (FA) ES+441. ¹H NMR (400 MHz, CDCl₃) δ: 8.29 (s, 1H), 5.54 (s, 2H), 3.71 (t,J=8.28 Hz, 2H), 0.95 (t, J=8.28 Hz, 2H), 0.00 (s, 9H).

Step 5:N-{4-[4-Bromo-5-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,2,4-triazol-3-yl)-1,3-thiazol-2-yl]pyridin-2-yl}acetamide

The mixture of3-(2,4-dibromo-1,3-thiazol-5-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,2,4-triazole(1.10 g, 2.50 mmol), N-[4-(trimethylstannyl)pyridin-2-yl]acetamide(0.896 g, 3.00 mmol), tetrakis(triphenylphosphine)palladium (0) (0.155g, 0.125 mmol), copper(I) iodide (0.143 g, 0.750 mmol) and lithiumchloride (0.318 g, 7.50 mmol) in dry 1,4-dioxane (100 mL) was sonicatedfor 2 min, degassed and backfilled with nitrogen 5 times. The mixturewas heated under nitrogen atmosphere to reflux for 90 min, then cooledto room temperature, filtered through celite and washed withdioxane/DCM. The filtrate was evaporated under reduced pressure to givea crude residue, which was purified by column chromatography on silicagel eluting with MeOH/DCM (0/100 to 5/95) to give a product, which wasfurther purified on a silica column using MeOH/EtOAc/hexane (0/0/100 to5/45/50) to give pure product (0.150 g, 13%). LCMS: (FA) ES+ 495, 497.¹H NMR (400 MHz, CDCl₃) δ: 8.72 (s, 1H), 8.37 (m, 1H), 8.33 (s, 1H),8.26 (s, 1H), 7.68 (m, 1H), 5.57 (s, 2H), 3.73 (t, J=8.28 Hz, 2H), 2.25(s, 3H), 0.97 (t, J=8.28 Hz, 2H), 0.00 (s, 9H).

Step 6:N-{4-[4-(4-Chlorobenzyl)-5-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,2,4-triazol-5-yl)-1,3-thiazol-2-yl]pyridin-2-yl}acetamide

To a solution ofN-{4-[4-bromo-5-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,2,4-triazol-5-yl)-1,3-thiazol-2-yl]pyridin-2-yl}acetamide(0.292 g, 0.589 mmol) in tetrahydrofuran (4.1 mL) was added4-chlorobenzylzinc chloride (0.50M solution in tetrahydrofuran, 2.36 mL,1.18 mmol) and bis(tri-t-butylphosphine)palladium(0) (0.0226 g, 0.0442mmol) under argon. The solution was stirred at 60° C. for 2 hours. Thereaction was incomplete by LCMS, so additional 4-chlorobenzylzincchloride (0.50M solution in tetrahydrofuran, 2 mL, 1 mmole) was added,then the reaction was stirred at 60° C. for an additional 2 hours. Thereaction was allowed to cool to room temperature then the solvent wasevaporated in vacuo. Column chromatography was performed to yield thetitle compound (0.112 g, 35%). LCMS: (FA) ES⁺ , 542. ¹H NMR (400 MHz,d₄-methanol) δ: 8.73-8.69 (m, 1H), 8.42-8.38 (m, 1H), 8.14 (s, 1H),7.58-7.55 (m, 1H), 7.27-7.20 (m, 4H), 5.52 (s, 2H), 4.32 (s, 2H),3.68-3.61 (m, 2H), 2.20 (s, 3H), 0.90-0.84 (m, 2H), 0.040 (s, 9H).

Step 7:N-{4-[4-(4-Chlorobenzyl)-5-(4H-1,2,4-triazol-3-yl)-1,3-thiazol-2-yl]pyridin-2-yl}acetamide(Compound 56)

To a solution ofN-{4-[4-(4-chlorobenzyl)-5-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,2,4-triazol-5-yl)-1,3-thiazol-2-yl]pyridin-2-yl}acetamide(0.112 g, 0.207 mmol) in dichloromethane (2.0 mL) at room temperaturewas added trifluoroacetic acid (3.1 mL, 40 mmol). The mixture was thenstirred at room temperature for 4 hours. The solvent was evaporated andthe excess trifluoroacetic acid was removed by azeotroping with toluene.Column chromatography was performed to yield the title compound (0.0520g, 61%). LCMS: (FA) ES⁺ , 411. ¹H NMR (400 MHz, d₆-DMSO) δ: 14.46 (s,1H), 10.69 (s, 1H), 8.80-8.73 (m, 1H), 8.64-8.60 (m, 1H), 8.43-8.37 (m,1H), 7.59-7.54 (m, 1H), 7.37-7.28 (m, 4H), 4.66 (s, 2H), 2.12 (s, 3H).

Compounds in the following table were prepared from the appropriatestarting materials in a method analogous to that of Example 13:

7 LCMS: (FA) ES+ 388, 390. 27 LCMS: (AA) ES+ 369, 371. 53 LCMS: (AA) ES+393, 395.

Example 14 Synthesis of3-[4-(4-chlorobenzyl)-5-(4H-1,2,4-triazol-3-yl)-1,3-thiazol-2-yl]-2-methylpyrazolo[1,5-a]pyridine(Compound 4)

Step 1:3-(4-Bromo-2-prop-1-yn-1-yl-1,3-thiazol-5-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,2,4-triazole

A mixture of3-(2,4-dibromo-1,3-thiazol-5-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,2,4-triazole(6.00 g, 13.6 mmol), lithium chloride (1.73 g, 40.9 mmol), copper(I)iodide (0.779 g, 4.09 mmol) and tetrakis(triphenylphosphine)platinum (0)(0.848 g, 0.681 mmol) in anhydrous 1,4-dioxane (120 mL, 1500 mmol) wassonicated under an argon atmosphere for 2 minutes in a 250 mL RBF.Tributyl(1-propynyl)tin (4.80 mL, 15.0 mmol) was added. The mixture washeated to 100° C. for 1 hour under an argon atmosphere. The mixture wascooled to rt., diluted with DCM (−150 mL), filtered through celite, andwashed with DCM. The filtrate was rotavaped to give a crude residuewhich was then purified by column chromatography (SiO2, elution with0-100% EtOAc in hexane) to afford a pure solid product (4.14 g, 76%yield). LCMS: (FA) ES⁺ 399, 401. ¹H NMR (400 MHz, CDCl₃) δ: 8.29 (s,1H), 5.54 (s, 2H), 3.69-3.74 (m, 2H), 2.15 (s, 3H), 0.93-0.97 (m, 2H),0.00 (s, 9H).

Step 2:3-[4-Bromo-5-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,2,4-triazol-3-yl)-1,3-thiazol-2-yl]-2-methylpyrazolo[1,5-a]pyridine

A mixture of3-(4-bromo-2-prop-1-yn-1-yl-1,3-thiazol-5-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,2,4-triazole(0.514 g, 1.29 mmol), 1-aminopyridinium iodide (0.343 g, 1.54 mmol) andpotassium carbonate (0.231 g, 1.67 mmol) in N,N-dimethylformamide (8.0mL, 1.0E2 mmol) was stirred at rt for 29 hours. The mixture was quenchedwith ice water (80 mL) then extracted with EtOAc 3 times. The combinedEtOAc solution was washed with water, brine, dried over Na₂SO₄, filteredand purified by column chromatography (SiO2, elution with 0-100% EtOAcin hexane) to afford a solid product. (0.410 g, 64.8% yield). LCMS: (FA)ES⁺ 491, 493. ¹H NMR (400 MHz, CDCl₃) δ: 8.43-8.46 (m, 2H), 8.32 (s,1H), 7.39-7.42 (m, 1H), 6.90-6.93 (m, 1H), 5.57 (m, 2H), 3.72-3.76 (m,2H), 2.76 (s, 3H), 0.96-1.00 (m, 2H), 0.00 (s, 9H).

Step 3:3-[4-(4-Chlorobenzyl)-5-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,2,4-triazol-3-yl)-1,3-thiazol-2-yl]-2-methylpyrazolo[1,5-c]pyridine

To a solution of3-[4-bromo-5-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,2,4-triazol-3-yl)-1,3-thiazol-2-yl]-2-methylpyrazolo[1,5-c]pyridine(0.200 g, 0.407 mmol) in tetrahydrofuran (2.8 mL) were added4-chlorobenzylzinc chloride (0.50M solution in tetrahydrofuran, 1.63 mL,0.814 mmol) and bis(tri-t-butylphosphine)palladium(0) (0.0156 g, 0.0305mmol) under argon. The solution was stirred at 60° C. for 3 hours. Thereaction was incomplete by LCMS, so additional 4-chlorobenzylzincchloride (0.50M solution in tetrahydrofuran, 1.0 mL, 0.5 mmole) wasadded then the reaction was stirred at 60° C. for an additional 3 hours.The reaction was cooled to room temperature then the solvent wasevaporated in vacuo. The residue was purified by column chromatography(SiO2, elution with EtOAc in hexanes 10-100% gradient) to yield thetitle compound (0.188 g, 86%). LCMS: (FA) ES⁺ , 538. ¹H NMR (400 MHz,d₆-DMSO) δ: 8.87 (s, 1H), 8.76-8.72 (m, 1H), 8.28-8.24 (m, 1H),7.54-7.48 (m, 1H), 7.44-7.40 (m, 2H), 7.35-7.30 (m, 2H), 7.09-7.03 (m,1H), 5.58 (s, 2H), 4.63 (s, 2H), 3.68-3.62 (m, 2H), 2.66 (s, 3H),0.91-0.84 (m, 2H), 0.050 (s, 9H).

Step 4:3-[4-(4-Chlorobenzyl)-5-(4H-1,2,4-triazol-3-yl)-1,3-thiazol-2-yl]-2-methylpyrazolo[1,5-c]pyridine(Compound 4)

To a solution of3-[4-(4-chlorobenzyl)-5-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,2,4-triazol-3-yl)-1,3-thiazol-2-yl]-2-methylpyrazolo[1,5-c]pyridine(0.182 g, 0.339 mmol) in dichloromethane (3.3 mL) at room temperaturewas added trifluoroacetic acid (5.1 mL, 66 mmol). The mixture was thenstirred at room temperature for 3 hours. The solvent was evaporated andthe excess trifluoroacetic acid was removed by azeotroping with toluene.The crude product was purified by column chromatography (SiO2, elutionwith hexane to 100% ethyl acetate) to yield the title compound (0.0884g, 64%). LCMS: (FA) ES⁺ , 407. ¹H NMR (400 MHz, d₆-DMSO) δ: 8.76-8.70(m, 2H), 8.28-8.22 (m, 1H), 7.53-7.46 (m, 1H), 7.45-7.40 (m, 2H),7.37-7.31 (m, 2H), 7.07-7.01 (m, 1H), 5.55-5.50 (m, 1H), 4.64 (s, 2H),2.65 (s, 3H).

Example 15 Synthesis ofN-{4-[4-benzyl-5-(1H-imidazol-2-yl)-1,3-thiazol-2-yl]pyridin-2-yl}acetamide(Compound 2)

Step 1: N-allyl-2,4-dibromo-1,3-thiazole-5-carboxamide

To a solution of 2,4-dibromo-1,3-thiazole-5-carboxylic acid (25.0 g,87.1 mmol) in dichloromethane (600 mL) at 0° C. was added thionylchloride (66.1 mL, 906 mmol) followed by N,N-dimethylformamide (7.02 mL,90.6 mmol). The mixture was allowed to warm to room temperature and stirfor 2 hours. The solvent was evaporated and the excess thionyl chloridewas removed by azeotroping with toluene. The residue was dissolved indichloromethane (600 mL) and cooled to 0° C., then added triethylamine(63.2 mL, 453 mmol) was added followed by 2-propen-1-amine (23.8 mL, 317mmol) and N,N-dimethylaminopyridine (1.11 g, 9.06 mmol). The mixture wasallowed to warm to room temperature and stirred for 2 hours. Thesolution was then diluted with dichloromethane and water and the layerswere separated. The aqueous phase was then extracted withdichloromethane twice, then the combined organic extracts were washedwith brine, dried over anhydrous sodium sulfate, filtered andconcentrated in vacuo. Column chromatography was performed to yield thetitle compound (14.3 g, 50%). LCMS: (FA) ES⁺ , 327. ¹H NMR (400 MHz,d₄-methanol) δ: 5.97-5.85 (m, 1H), 5.32-5.24 (m, 1H), 5.20-5.14 (m, 1H),4.02-3.95 (m, 2H).

Step 2: 5-(1-allyl-1H-imidazol-2-yl)-2,4-dibromo-1,3-thiazole

To a solution of N-allyl-2,4-dibromo-1,3-thiazole-5-carboxamide (13.0 g,39.9 mmol) in dichloromethane (260 mL) was added phosphoruspentachloride (9.93 g, 47.7 mmol) and 4M hydrochloric acid in dioxane(1.52 mL, 6.06 mmol). The reaction was heated to 60° C. for 90 minutesunder an atmosphere on nitrogen. The reaction was allowed to cool toroom temperature and then aminoacetaldehyde dimethyl acetal (47.8 mL,439 mmol) was added slowly through the condenser. The mixture was heatedto 60° C. for 2 hours under an atmosphere of nitrogen then cooled toroom temperature, and water was added (200 mL). The layers wereseparated and the organic phase was washed with water again (2×200 mL).The organic extracts were washed with brine, dried over anhydrous sodiumsulfate, filtered and washed with dichloromethane (200 mL). To thisdichloromethane solution of the intermediate was added 4M hydrochloricacid in dioxane (120 mL, 480 mmol) and the solution was stirred at 60°C. for 16 hours. The solution was decanted (leaving behind an oily blackresidue on the flask) then the solvent was evaporated and the residuewas diluted with ethyl acetate and saturated sodium bicarbonatesolution. The layers were separated and the aqueous phase was extractedthree more times with ethyl acetate. The organic extracts were washedwith brine, dried over anhydrous sodium sulfate, filtered andconcentrated in vacuo. Column chromatography was performed to yield thetitle compound (8.04 g, 58%). LCMS: (FA) ES⁺ , 306 (parent minus allylgroup). ¹H NMR (300 MHz, d₄-methanol) δ: 7.37-7.31 (m, 1H), 7.20-7.16(m, 1H), 6.02-5.86 (m, 1H), 5.26-5.18 (m, 1H), 5.07-4.96 (m, 1H),4.68-4.59 (m, 2H).

Step 3: Synthesis ofN-{4-[5-(1-allyl-1H-imidazol-2-yl)-4-bromo-1,3-thiazol-2-yl]pyridin-2-yl}acetamide

To a solution of 5-(1-allyl-1H-imidazol-2-yl)-2,4-dibromo-1,3-thiazole(5.00 g, 14.3 mmol) in 1,4-dioxane (133 mL) was addedN-[4-(trimethylstannyl)pyridine-2-yl]acetamide (5.14 g, 17.2 mmol),lithium chloride (1.82 g, 43.0 mmol), copper (I) iodide (0.818 g, 4.30mmol) and tetrakis (triphenylphosphine)palladium(0) (1.24 g, 1.07 mmol).The flask was purged with argon and then the mixture was heated at 115°C. for 4 hours. The reaction was allowed to cool to room temperature,and then the solvent was evaporated in vacuo. Column chromatography wasperformed to yield the title compound (3.13 g, 54%). LCMS: (FA) ES⁺ ,406. ¹H NMR (400 MHz, d₆-DMSO) δ: 10.77 (s, 1H), 8.66-8.61 (m, 1H),8.49-8.44 (m, 1H), 7.61-7.56 (m, 1H), 7.49-7.45 (m, 1H), 5.98-5.87 (m,1H), 5.19-5.12 (m, 1H), 4.95-4.88 (m, 1H), 4.70-4.64 (m, 2H), 2.13 (s,3H).

Step 4: Synthesis ofN-{4-[5-(1-allyl-1H-imidazol-2-yl)-4-benzyl-1,3-thiazol-2-yl]pyridin-2-yl}acetamide

To a solution ofN-{4-[5-(1-allyl-1H-imidazol-2-yl)-4-bromo-1,3-thiazol-2-yl]pyridin-2-yl}acetamide(0.0500 g, 0.124 mmol) in tetrahydrofuran (0.86 mL) was added benzylzincbromide (0.50M solution in tetrahydrofuran, 0.495 mL, 0.247 mmol) andbis(tri-t-butylphosphine)palladium(0) (0.00474 g, 0.00928 mmol) underargon. The solution was stirred at 60° C. for 2 hours then cooled toroom temperature. The solvent was evaporated in vacuo. Columnchromatography was performed to yield the title compound (0.0110 g,21%). LCMS: (FA) ES⁺ , 416. ¹H NMR (400 MHz, d₄-methanol) δ: 8.70-8.65(m, 1H), 8.41-8.36 (m, 1H), 7.66-7.61 (m, 1H), 7.34-7.05 (m, 7H),5.81-5.70 (m, 1H), 5.16-5.10 (m, 1H), 4.95-4.88 (m, 1H), 4.38-4.33 (m,2H), 4.13 (s, 2H), 2.20 (s, 3H).

Step 5: Synthesis ofN-{4-[4-benzyl-5-(1H-imidazol-2-yl)-1,3-thiazol-2-yl]pyridin-2-yl}acetamide(Compound 2)

To a solution ofN-{4-[5-(1-allyl-1H-imidazol-2-yl)-4-benzyl-1,3-thiazol-2-yl]pyridin-2-yl}acetamide(0.210 g, 0.0505 mmol) in dichloromethane (0.38 mL) and acetic acid(0.13 mL) was added tetrakis (triphenylphosphine)palladium(0) (0.00292g, 0.00253 mmol) followed by phenylsilane (0.0318 mL, 0.258 mmol). Thesolution was stirred at 40° C. for 3 hours. The solution was cooled toroom temperature then concentrated in vacuo and diluted with ethylacetate and saturated sodium bicarbonate solution. The layers wereseparated and the aqueous phase was extracted three more times withethyl acetate. The organic extracts were washed with brine, dried overanhydrous sodium sulfate, filtered and concentrated in vacuo. Columnchromatography was performed to yield the title compound (0.0100 g,53%). LCMS: (FA) ES⁺ , 376. ¹H NMR (400 MHz, d₄-methanol) δ: 8.67-8.63(m, 1H), 8.38-8.35 (m, 1H), 7.63-7.59 (m, 1H), 7.25-7.07 (m, 7H), 4.42(s, 2H), 2.20 (s, 3H).

Compounds in the following table were prepared from the appropriatestarting materials in a method analogous to that of Example 15:

24 LCMS: (FA) ES+ 390 67 LCMS: (FA) ES+ 410, 412. 73 LCMS: (FA) ES+ 410,412.

Example 16 Synthesis of(4-chlorophenyl)[2-pyridin-4-yl-5-(1H-1,2,4-triazol-3-yl)-1,3-thiazol-4-yl]methanol(Compounds 19 and 70)

Step 1:4-[5-(1-{[2-(Trimethylsilyl)ethoxy]methyl}-1H-1,2,4-triazol-3-yl)-4-vinyl-1,3-thiazol-2-yl]pyridine

Into a sealed tube was added potassium vinyltrifluoroborate (1.34 g,10.0 mmol), 1,4-dioxane (21.0 mL, 269 mmol),4-[4-bromo-5-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,2,4-triazol-3-yl)-1,3-thiazol-2-yl]pyridine(2.0 g, 4.6 mmol) and 2 M sodium carbonate in water (9.10 mL, 18.2mmol). The reaction was degassed with nitrogen for 15 min thentetrakis(triphenylphosphine)palladium(0) (527 mg, 0.456 mmol) was added.The tube was sealed and the reaction was heated in an oil bath at 110°C. with stirring overnight. The reaction solution was cooled to roomtemperature, water (10 mL) and EtOAc (10 mL) were added, and thecombined organic layers were washed with brine, dried over MgSO₄,filtered and concentrated under reduced pressure. The obtained residuewas purified by column chromatography (SiO₂, elution with 0-10% MeOH inDCM) to give the title compound as a yellow solid (1.34 g 81%). LCMS:(FA) ES⁺ , 386. ¹H NMR (400 MHz, d6-DMSO) δ: 8.92 (s, 1H), δ 8.74-8.76(dd, J=1.75 Hz, J=1.5 Hz 2H), 7.96-7.98 (dd, J=1.75 Hz, 2H), 6.34-6.40(dd, J=2.3 Hz, 12H), 5.62-5.65 (dd, J=2.3 Hz, 1H), 5.60 (s, br, 2H),3.63-3.68 (m, 2H), 0.86-0.90 (m, 2H), −0.04 (s, 9H).

Step 2:2-Pyridin-4-yl-5-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,2,4-triazol-3-yl)-1,3-thiazole-4-carbaldehyde

To a solution of4-[5-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,2,4-triazol-3-yl)-4-vinyl-1,3-thiazol-2-yl]pyridine(1.43 g, 2.60 mmol) in a 3:1 mixture of 1,4-dioxane (17.5 mL, 224.6mmol) and water (5.8 mL, 324.25 mmol) was added 2,6-lutidine (1.50 mL,12.98 mmol) and the mixture was cooled to 0° C. Sodium metaperiodate(2.80 g, 12.98 mmol) was added followed by the addition of 4% osmiumtetroxide in water (0.50 mL, 0.080 mmol) and the reaction mixture wasslowly warmed to ambient temperature and allowed to stir overnight.Water (10 mL) was added. The resulting yellow precipitate was collectedby filtration, washed with water, ether and MeOH. The filtrate wasconcentrated under reduced pressure and dried on the high vac to givethe title compound (1.0 g, yield 99%). LCMS: (FA) ES⁺ , 388. ¹H NMR (400MHz, d₆-DMSO) δ: 10.70 (s, 1H), 6:9.05 (s, 1H), 8.79-8.80 (dd, J=1.5 Hz,2H), 7.98-8.0 (dd, J=1.5 Hz, J=1.7 Hz, 2H), 5.64-5.66 (s, br, 2H),3.64-3.68 (m, 2H), 0.870-0.90 (m, 2H), −0.03 (s, 9H).

Step 3:(4-Chlorophenyl)[2-pyridin-4-yl-5-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,2,4-triazol-3-yl)-1,3-thiazol-4-yl]methanol

To a solution of2-pyridin-4-yl-5-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,2,4-triazol-3-yl)-1,3-thiazole-4-carbaldehyde(280.0 mg, 0.722 mmol) in tetrahydrofuran (4.0 mL, 40 mmol), 1 M4-chlorophenyl magnesium bromide in ether (4.0 mL, 4 mmol) was added andthe mixture was stirred for 40 min at rt. After the reaction wascompleted a 5% aqueous solution of NH₄Cl (10 mL) and EtOAc (10 mL) wereadded and the resulting bi-phasic mixture was vigorously stirred for 15min then the aqueous phase was discarded. The organic phase was washedwith brine (5 mL) then dried over anhydrous MgSO₄. Insoluble materialswere removed by filtration and the filtrate was concentrated underreduced pressure. The obtained residue was purified by columnchromatography (SiO₂, elution with 20-80% EtOAc in hexane) to give thetitle compound as a white solid (230 mg, 73.6%). LCMS: (FA) ES⁺ , 500.¹H NMR (400 MHz, d₆-DMSO) δ: 8.96 (s, 1H), δ 8.70-8.72 (dd, J=1.75 Hz,2H), 7.87-7.89 (dd, J=1.75, 2H), 7.32-7.37 (m, 2H), 7.55-7.58 (m, 3H),6.85-6.87 (d, J=5.5 Hz, 1H), 6.15-6.17 (d, J=5.5 Hz, 1H), 5.6 (s, br,2H), 3.65-3.67 (m, 2H), 0.850-0.90 (m, 2H), −0.05 (s, 9H).

Step 4:(4-Chlorophenyl)[2-pyridin-4-yl-5-(1H-1,2,4-triazol-3-yl)-1,3-thiazol-4-yl]methanol

(4-Chlorophenyl)[2-pyridin-4-yl-5-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,2,4-triazol-3-yl)-1,3-thiazol-4-yl]methanol(266.0 mg, 0.530 mmol) was dissolved in methylene chloride (3.0 mL, 47mmol). Trifluoroacetic acid (3.0 mL, 39 mmol) was added and the solutionwas stirred at rt overnight. After the reaction was completed, saturatedNaHCO₃ was added and the reaction was stirred at rt for 20 min, thenEtOAc (5 mL) was added, the organic layer was separated, washed withbrine, dried over MgSO₄, filtered, concentrated and the obtained residuewas purified by column chromatography (SiO₂, elution with 2-20% MeOH inDCM) to give the title compound as a white solid (200 mg). The racemicisomers were separated by chiral prep HPLC to yield 17 (34 mg, 12.7%)(peak 1, ret. time 13.04 min). LCMS: (FA) ES⁺ , 370. ¹H NMR (400 MHz,d₆-DMSO) δ: 8.76 (s, 1H), 8.69-8.71 (dd, J=1.5 Hz, 2H), 7.86-7.88 (dd,J=1.5, 2H), 7.55-7.58 (d, J=8.5 Hz, 2H), 7.34-7.38 (d, J=8.5 Hz, 2H),6.84-6.86 (s, br, 1H) and 70 (34.8 mg, 13.0%) (peak 2, ret. time 13.2min). LCMS: (FA) ES⁺ , 370. ¹H NMR (400 MHz, d₆-DMSO) δ: 8.68-8.72 (m,3H), 7.86-7.88 (dd, J=1.69 Hz, J=1.5 Hz, 2H), 7.54-7.58 (d, J=8.47 Hz,2H), 7.34-7.38 (d, J=8.47 Hz, 2H), 6.81-6.82 (s, br, 1H).

Compounds in the following table were prepared from the appropriatestarting materials in a method analogous to that of Example 16:

149 LCMS: (AA) ES+ 451, 453, 455 168 LCMS: (FA) ES+ 418, 420 238 LCMS:(AA) ES+ 427, 429 265 LCMS: (AA) ES+ 431, 433 278 LCMS: (AA) ES+ 451,453, 455 282 LCMS: (FA) ES+ 418, 420 285 LCMS: (AA) ES+ 431, 433

Example 17 Synthesis of4-(4-chlorobenzyl)-5-(1H-imidazol-2-yl)-2-(pyridin-4-yl)thiazole(Compound 15)

Step 1:N-Allyl-4-(4-chlorobenzyl)-2-(pyridin-4-yl)thiazole-5-carboxamide

To a stirred solution of4-(4-chlorobenzyl)-2-(pyridin-4-yl)thiazole-5-carboxylic acid (220 mg,0.665 mmol) in DCM (4.05 mL) was added HOBT (98.8 mg, 0.732 mmol) andEDCI (204 mg, 1.06 mmol) at room temperature and the mixture was stirredfor 30 min. To the solution was added 2-propen-1-amine (0.200 mL, 2.66mmol) then the resulting mixture was stirred at room temperatureovernight. The reaction mixture was diluted with DCM (10 mL) and washedwith water (3 mL) and brine (2 mL), then dried over MgSO₄, filtered, andconcentrated in vacuo. The residue was purified by silica gelchromatography (ethyl acetate/DCM=0/100→75/25) to give 150 mg of thetitle compound as a yellow solid (61% yield). LCMS (FA) ES+ 370. ¹H NMR(400 MHz, CDCl₃) δ: 8.74-8.72 (m, 2H), 7.79-7.77 (m, 2H), 7.35-7.32 (m,2H), 7.27-7.25 (m, 2H), 5.94-5.80 (m+bs, 2H), 5.25-5.20 (m, 2H), 4.48(s, 2H), 4.06-4.02 (m, 2H).

Step 2:5-(1-Allyl-1H-imidazol-2-yl)-4-(4-chlorobenzyl)-2-(pyridin-4-yl)thiazole

To a solution ofN-allyl-4-(4-chlorobenzyl)-2-(pyridin-4-yl)thiazole-5-carboxamide (150mg, 0.406 mmol) in DCM (2.64 mL) was added phosphorus pentachloride (101mg, 0.485 mmol) and 4 M hydrochloric acid in 1,4-dioxane (0.0154 mL,0.0614 mmol) and the mixture was heated to 60° C. for 1.5 h. Thereaction was cooled to room temperature and aminoacetaldehyde dimethylacetal (0.486 mL, 4.46 mmol) was added. The resulting mixture was heatedat 60° C. for 2 h. The mixture was cooled to room temperature, dilutedwith DCM (10 mL), washed with water (2×2 mL) and brine (2 mL), driedover sodium sulfate, filtered, and concentrated in vacuo. The residuewas taken up in DCM (3.0 mL) and 4 M hydrochloric acid in 1,4-dioxane(0.608 mL, 2.43 mmol) was added and the mixture was stirred at 60° C.overnight. The reaction was cooled and concentrated in vacuo. Theresidue was taken up in ethyl acetate (20 mL) and saturated sodiumbicarbonate (5 mL). The layers were separated and the aqueous layer wasextracted with ethyl acetate (5 mL). The combined organic layers weredried over MgSO₄, filtered, and concentrated in vacuo. The residue waspurified by silica gel chromatography (methanol/DCM=0/100→5/95) to give99 mg of the title compound (62% yield). LCMS (FA) ES+ 393. ¹H NMR (300MHz, CDCl₃) δ: 8.72-8.70 (m, 2H), 7.80-7.72 (m, 2H), 7.26 (m, 1H),7.22-7.14 (m, 4H), 7.06 (m, 1H), 5.84-5.71 (m, 1H), 5.23-5.19 (m, 1H),5.01-4.96 (m, 1H), 4.38-4.34 (m, 2H), 4.20 (s, 2H).

Step 3:4-(4-Chlorobenzyl)-5-(1H-imidazol-2-yl)-2-(pyridin-4-yl)thiazole,hydrochloride salt (Compound 15)

To a solution of5-(1-allyl-1H-imidazol-2-yl)-4-(4-chlorobenzyl)-2-(pyridin-4-yl)thiazole(99.0 mg, 0.252 mmol) and tetrakis(triphenylphosphine)palladium (14.6mg, 0.0126 mmol) in DCM (3.38 mL) was added acetic acid (0.623 mL, 11.0mmol) and phenylsilane (0.158 mL, 1.28 mmol) and the mixture was stirredfor 2 h at 40° C. The reaction mixture was evaporated to removevolatiles and DCM (10 mL) added. To this solution was added saturatedsodium bicarbonate (4 mL) and the resulting mixture was stirred for 30min. The mixture was extracted with DCM (3×10 mL) and the combined DCMlayers were washed with brine. The organics were dried over MgSO₄,filtered, and concentrated in vacuo. The residue was purified by silicagel chromatography (methanol/DCM=0/100→10/90) to give 57 mg of the titlecompound as a yellow solid (64% yield). The HCl salt was made asfollows. To a mixture of the free base (57 mg, 0.162 mmol) in ethanol (5mL) was added 1.0 M HCl in ether (0.178 mL, 0.178 mmol) and the mixturewas stirred for 2 hours then concentrated in vacuo. The residue wastaken up in a minimum of methanol, and acetonitrile was added to give aprecipitate. Ether was added and the precipitate was filtered, washedwith ether and dried to give the title compound as an orange solid. LCMS(FA) ES+ 353. ¹H NMR (400 MHz, d₆-DMSO) δ: 8.78-8.74 (m, 2H), 7.96-7.91(m, 2H), 7.48-7.43 (m, 2H), 7.34-7.28 (m, 4H), 4.51 (s, 2H).

Example 18 Synthesis of4-(4-chlorobenzyl)-5-(1H-imidazol-5-yl)-2-(pyridin-4-yl)thiazole(Compound 66)

Step 1:4-(4-Chlorobenzyl)-N-methoxy-N-methyl-2-(pyridin-4-yl)thiazole-5-carboxamide

To a solution of4-(4-chlorobenzyl)-2-(pyridin-4-yl)thiazole-5-carboxylic acid (850 mg,2.57 mmol) in DMF (11.9 mL) was added N,O-dimethylhydroxylaminehydrochloride (852 mg, 8.74 mmol), HATU (1.95 g, 5.14 mmol) anddiisopropylethylamine (2.42 mL, 13.9 mmol) and the resulting solutionwas stirred at room temperature overnight. The reaction was diluted withwater (30 mL) and extracted with ethyl acetate (2×25 mL). The combinedorganic layers were washed with water (3×30 mL), dried over MgSO₄,filtered, and concentrated in vacuo. The residue was purified by silicagel chromatography (ethyl acetate/DCM=0/100→80/20) to give 775 mg of thetitle compound as a yellow solid (80% yield). LCMS (FA) ES+ 374. ¹H NMR(400 MHz, CDCl₃) δ: 8.72-8.70 (m, 2H), 7.84-7.82 (m, 2H), 7.37-7.34 (m,2H), 7.25-7.22 (m, 2H). 4.56 (s, 2H), 3.70 (s, 3H), 3.37 (s, 3H).

Step 2: Preparation of4-(4-chlorobenzyl)-2-(pyridin-4-yl)thiazole-5-carbaldehyde

To a solution of4-(4-chlorobenzyl)-N-methoxy-N-methyl-2-(pyridin-4-yl)thiazole-5-carboxamide(1.13 g, 3.02 mmol) in THF (36.8 mL) at −50° C. was added 1.0 Mdiisobutylaluminum hydride in hexane (15.1 mL, 15.1 mmol) and theresulting solution was stirred at −50° C. to −30° C. for 2 hours. Thereaction was quenched with saturated ammonium chloride (10 mL) andallowed to warm to room temperature. Water (25 mL) was added and themixture was extracted with ethyl acetate (2×40 mL). The combined organiclayers were dried over MgSO₄, filtered, and concentrated in vacuo. Theresidue was purified by silica gel chromatography (ethylacetate/DCM=0/100→70/30) to give 699 mg of the title compound as a whitesolid (73% yield). LCMS (FA) ES+ 315. ¹H NMR (300 MHz, CDCl₃) δ: 10.16(s, 1H), 8.78-8.76 (m, 2H), 7.85-7.83 (m, 2H), 7.30-7.25 (m, 4H), 4.47(s, 2H).

Step 3:N′-{(1E)-[4-(4-chlorobenzyl)-2-pyridin-4-yl-1,3-thiazol-5-yl]methylene}-N,N-dimethylsulfamide

A solution of 4-(4-chlorobenzyl)-2-(pyridin-4-yl)thiazole-5-carbaldehyde(186 mg, 0.591 mmol) and N,N-dimethylsulfonamide ((75.6 mg, 0.608 mmol)(prepared according to Li, Tetrahedron Letters, 50(19), 2232-2235) intoluene (5.0 mL) was refluxed overnight using a Dean Stark trap toazeotrope water. The reaction was cooled and concentrated in vacuo. Theresidue was purified by silica gel chromatography (ethylacetate/DCM=0/100→60/40) to give 699 mg of the title compound as ayellow solid (60% yield). LCMS (FA) ES+ 421. ¹H NMR (300 MHz, CDCl₃) δ:9.08 (s, 1H), 8.78-8.76 (m, 2H), 7.84-7.82 (m, 2H), 7.32-7.22 (m, 4H),4.38 (s, 2H), 2.86 (s, 6H).

Step 4:5-(4-(4-Chlorobenzyl)-2-(pyridin-4-yl)thiazol-5-yl)-N,N-dimethyl-1H-imidazole-1-sulfonamideand 4-(4-chlorobenzyl)-5-(1H-imidazol-5-yl)-2-(pyridin-4-yl)thiazole(Compound 66)

A solution ofN′-{(1E)-[4-(4-chlorobenzyl)-2-pyridin-4-yl-1,3-thiazol-5-yl]methylene}-N,N-dimethylsulfamide(148 mg, 0.352 mmol), p-tolylsulfonylmethyl isocyanide (75.5 mg, 0.387mmol) and potassium carbonate (146 mg, 1.05 mmol) in DME (2.50 mL) washeated at 78° C. for 2 hours. The reaction was diluted with DCM (10 mL)and water (5 mL). The layers were separated and the aqueous layer wasextracted with DCM (5 mL). The combined organic layers were dried overMgSO₄, filtered, and concentrated in vacuo. The residue was purified bysilica gel chromatography (methanol/DCM=0/100→15/85) to give 50 mg of5-(4-(4-chlorobenzyl)-2-(pyridin-4-yl)thiazol-5-yl)-N,N-dimethyl-1H-imidazole-1-sulfonamide.LC/MS (FA) ES+ 460. (Some of the deprotected product,4-(4-chlorobenzyl)-5-(1H-imidazol-5-yl)-2-(pyridin-4-yl)thiazole, wasalso obtained (19 mg). This material was combined with the materialobtained in the following deprotection step.)

A solution of5-(4-(4-chlorobenzyl)-2-(pyridin-4-yl)thiazol-5-yl)-N,N-dimethyl-1H-imidazole-1-sulfonamide(50 mg, 0.109 mmol) in 48% HBr in water (3.0 mL) was heated to 90° C.for 2.5 hours. The cooled solution was taken up in DCM (20 mL) andsaturated sodium bicarbonate (20 mL). The layers were separated and theaqueous extracted with DCM (20 mL). The combined organic layers weredried over MgSO₄, filtered, and concentrated in vacuo. To this crudematerial was added the 19 mg of deprotected material obtained in theprevious step. The combined material was purified by silica gelchromatography (methanol/DCM=0/100→15/85) to give 34 mg of the titlecompound as a white solid (27% yield). LCMS (FA) ES+ 353. ¹H NMR (300MHz, d₄-MeOH) δ: 8.63-8.61 (m, 2H), 7.93-7.91 (m, 2H), 7.80 (d, 1H,J=1.1 Hz), 7.30-7.19 (m, 5H), 4.35 (s, 2H).

Example 19 Synthesis of4-(4-chlorobenzyl)-2-(pyridin-4-yl)-5-(1H-pyrrol-2-yl)thiazole (Compound22)

Step 1: 1-Bromo-3-(4-chlorophenyl)propan-2-one

To a solution of 1-(4-chlorophenyl)propan-2-one (25.0 g, 148 mmol) inacetic acid (37.9 mL) was added 48% aqueous HBr (19.0 mL, 168 mmol). Asolution of bromine (16.3 mL, 316 mmol) in acetic acid (63.2 mL) wasthen added over 10 minutes and the resulting solution was stirred for 4hours at room temperature. Acetone (190 mL) was added and the resultingsolution was stirred at room temperature for 3 days. The reaction wasconcentrated in vacuo and the residue was taken up in DCM (300 mL) andbrine (100 mL). The layers were separated and the aqueous layer wasextracted with DCM (100 mL). The combined organic layers were dried overMgSO₄, filtered, and concentrated in vacuo. The residue was purified bysilica gel chromatography (ethyl acetate/hexanes=0/100→15/85) to give25.4 grams of the title compound as a dark gray solid (69% yield). ¹HNMR (400 MHz, CDCl₃) δ: 7.34-7.31 (m, 2H), 7.18-7.15 (m, 2H), 3.94 (s,2H), 3.91 (2, 2H).

Step 2: 4-(4-Chlorobenzyl)thiazol-2-amine

A mixture of 1-bromo-3-(4-chlorophenyl)propan-2-one (25.4 grams, 103mmol) and thiourea (8.59 g, 113 mmol) in ethanol (1.51 L) was heated at85° C. for 2 hours. The reaction was cooled and concentrated in vacuoand the residue was taken up in ethyl acetate (300 mL) and saturatedsodium bicarbonate (100 mL). The layers were separated and the aqueouslayer was extracted with ethyl acetate (100 mL). The combined organiclayers were washed with brine (50 mL), dried over MgSO₄, filtered, andconcentrated in vacuo. The residue was recrystallized from ethylacetate/hexanes to give 19.9 grams of the title compound as a tan powder(86% yield). LCMS (FA) ES+ 225. ¹H NMR (300 MHz, CDCl₃) δ: 7.29-7.24 (m,2H), 7.20-7.15 (m, 2H), 6.04 (m, 1H), 5.00 (bs, m, 2H), 3.83 (s, 2H).

Step 3: 2,5-Dibromo-4-(4-chlorobenzyl)thiazole

To a mixture of 4-(4-chlorobenzyl)thiazol-2-amine (6.90 g, 30.7 mmol) inacetonitrile (367 mL) was added copper(II) bromide (10.3 grams, 46.0mmol) and the resulting mixture was stirred at room temperature for 4hours. Butyl nitrite (5.21 mL, 46.0 mmol) was added and the mixture wasstirred at room temperature for 30 minutes. The reaction wasconcentrated in vacuo and the residue was slurried in DCM (250 mL) for30 minutes. The mixture was filtered through Celite and washed with DCM(50 mL). The filtrate was concentrated in vacuo and the residue waspurified by silica gel chromatography (ethylacetate/hexanes=0/100→10/90) to give 8.47 grams of the title compound asan orange oil (75% yield). LCMS (FA) ES+ 368, 370. ¹H NMR (300 MHz,CDCl₃) δ: 7.30-7.18 (m, 4H), 4.03 (s, 2H).

Step 4: 5-Bromo-4-(4-chlorobenzyl)-2-(pyridin-4-yl)thiazole

To a solution of 2,5-dibromo-4-(4-chlorobenzyl)thiazole (12.9 grams,35.1 mmol) in DME (365 mL) was added pyridine-4-boronic acid (5.61 g,45.6 mmol), 1M sodium carbonate (70.2 mL, 70.2 mmol), and PdCl₂(dppf)(2.89 g, 3.51 mmol). The reaction was degassed with argon and stirred at85° C. overnight. The reaction was cooled and taken up in ethyl acetate(400 mL) and saturated sodium bicarbonate (200 mL). The insolubles werefiltered through celite and the bed was washed with ethyl acetate (100mL). The layers were separated and the aqueous layer was extracted withethyl acetate (100 mL). The combined organic layers were dried overMgSO₄, filtered, and concentrated in vacuo. The residue was purified bysilica gel chromatography (ethyl acetate/DCM=0/100→70/30) followed byanother silica gel chromatography (ethyl acetate/hexanes=0/100→100/0) togive 3.3 grams of the title compound as a brown solid (26% yield). LCMS(FA) ES+ 365, 367. ¹H NMR (300 MHz, CDCl₃) δ: 8.70-8.67 (m, 2H),7.70-7.67 (m, 2H), 7.28-7.26 (m, 4H), 4.13 (s, 2H).

Step 5: 4-(4-Chlorobenzyl)-2-(pyridin-4-yl)-5-(1H-pyrrol-2-yl)thiazole(Compound 22)

To a solution of 5-bromo-4-(4-chlorobenzyl)-2-(pyridin-4-yl)thiazole(94.0 mg, 0.257 mmol) in 4:1 dioxane:water (3.0 mL) was added1-(t-butoxycarbonyl)pyrrole-2-boronic acid (57 mg, 0.27 mmol), cesiumcarbonate (251 mg, 0.771 mmol), andtetrakis(triphenylphosphine)palladium(0) (30 mg, 0.026 mmol). Thesolution was degassed with argon and heated in a microwave reactor at130° C. for 105 minutes. The reaction was concentrated in vacuo and theresidue taken up in DCM (25 mL) and water (10 mL). The layers wereseparated and the aqueous layer was extracted with DCM (2×10 mL). Thecombined organic layers were dried over MgSO₄, filtered, andconcentrated in vacuo. The residue was purified by silica gelchromatography (ethyl acetate/DCM=0/100→80/20) followed by HPLCpurification (formic acid method) to give 26 mg of the title compound asa yellow solid (29% yield). LCMS (FA) ES+ 352. ¹H NMR (300 MHz, d₄-MeOH)δ: 8.62-8.60 (m, 2H), 7.90-7.88 (m, 2H), 7.66-7.55 (m, 1H), 7.26-7.24(m, 2H), 7.20-7.17 (m, 2H), 6.92 (dd, 1H, J=2.7, 1.5 Hz), 6.32 (dd, 1H,J=3.5, 1.5 Hz), 6.21 (dd, 1H, J=3.5, 2.7 Hz), 4.28 (s, 2H).

Example 20 Synthesis of4-(4-chlorobenzyl)-2-(2-chloropyridin-4-yl)-5-(4H-1,2,4-triazol-3-yl)thiazole(Compound 47)

Step 1: 4-(4-(4-Chlorobenzyl)-5-(methoxycarbonyl)thiazol-2-yl)pyridine1-oxide

To a solution of ethyl4-(4-chlorobenzyl)-2-(pyridin-4-yl)thiazole-5-carboxylate (430 mg, 1.20mmol) in DMF (6.0 mL) was added mCPBA (322 mg, 1.44 mmol) and themixture was stirred at room temperature overnight. To the reaction wasadded DCM (30 mL) and saturated sodium bicarbonate (25 mL). The layerswere separated and the aqueous layer extracted with DCM (20 mL). Thecombined organic layers were dried over MgSO₄, filtered, andconcentrated in vacuo. The residue was purified by silica gelchromatography (ethyl acetate/DCM=50/50→100/0) to give 449 mg of thetitle compound as a white solid (100% yield). LCMS (FA) ES+ 375. ¹H NMR(300 MHz, CDCl₃) δ: 8.23-8.20 (m, 2H), 7.84-7.81 (m, 2H), 7.33-7.23 (m,4H), 4.51 (s, 2H), 4.38 (q, 2H, J=7.2 Hz), 1.39 (t, 3H, J=7.2 Hz).

Step 2: Ethyl4-(4-chlorobenzyl)-2-(2-chloropyridin-4-yl)thiazole-5-carboxylate

A solution of4-(4-(4-chlorobenzyl)-5-(methoxycarbonyl)thiazol-2-yl)pyridine 1-oxide(334 mg, 0.891 mmol) in phosphoryl chloride (1.66 mL, 17.8 mmol) washeated at 100° C. for 2 hours. The reaction was cooled and poured ontoice and saturated sodium bicarbonate (50 mL). The mixture was extractedwith ethyl acetate (2×40 mL) and the combined organic layers were washedwith water (20 mL), brine (10 mL) and dried over MgSO₄, filtered, andconcentrated in vacuo. The residue was purified by silica gelchromatography (DCM/hexanes=50/50→100/0) to give 191 mg of the titlecompound as a white solid (54% yield). LCMS (FA) ES+ 393, 395. ¹H NMR(300 MHz, CDCl₃) δ: 8.49 (dd, 1H, J=5.3, 0.7 Hz), 7.88 (dd, 1H, J=1.5,0.7 Hz), 7.71 (dd, 1H, J=5.3, 1.5 Hz), 7.36-7.31 (m, 2H), 7.27-7.23 (m,2H), 4.53 (s, 2H), 4.39 (q, 2H, J=7.2 Hz), 1.40 (t, 3H, J=7.2 Hz).

Step 3: 4-(4-Chlorobenzyl)-2-(2-chloropyridin-4-yl)thiazole-5-carboxylicacid

To a solution of ethyl4-(4-chlorobenzyl)-2-(2-chloropyridin-4-yl)thiazole-5-carboxylate (199mg, 0.506 mmol) in THF (2.84 mL) and water (1.42 mL) was added 1.0 MLiOH (0.658 mL, 0.658 mmol) and the resulting solution was stirred atroom temperature overnight. The mixture was acidified to pH=4 with 1 NHCl. The precipitated solids were filtered, washed with water and driedto give 179 mg of the title compound as an a white solid. (96% yield).LCMS (FA) ES+ 365, 367.

Step 4:4-(4-Chlorobenzyl)-2-(2-chloropyridin-4-yl)thiazole-5-carboxamide

To a mixture of4-(4-chlorobenzyl)-2-(2-chloropyridin-4-yl)thiazole-5-carboxylic acid(179 mg, 0.490 mmol) in DCM (27.5 mL) was added EDCI (282 mg, 1.47 mmol)and 1-hydroxybenzotriazole hydrate (150 mg, 0.980 mmol) and the solutionwas stirred for 10 minutes. 28% ammonium hydroxide (2.12 mL, 24.5 mmol)was added and the resulting mixture was stirred at room temperatureovernight. Water (20 mL) was added and the mixture was extracted withDCM (2×25 mL). The combined organic layers were dried over MgSO₄,filtered, and concentrated in vacuo. The residue was purified by silicagel chromatography (methanol/DCM=0/100→15/85) to give 121 mg of thetitle compound as a white solid (67% yield). LCMS (FA) ES+ 364, 366. ¹HNMR (400 MHz, d₆-DMSO) δ: 8.54 (dd, 1H, J=5.2, 0.7 Hz), 8.02 (bs, 1H),7.91 (dd, 1H, J=1.5, 0.7 Hz), 7.84 (dd, 1H, J=5.2, 1.5 Hz), 7.79 (bs,1H), 7.36-7.29 (m, 4H), 4.43 (s, 2H).

Step 5:4-(4-Chlorobenzyl)-2-(2-chloropyridin-4-yl)-5-(4H-1,2,4-triazol-3-yl)thiazole(Compound 47)

A solution of4-(4-chlorobenzyl)-2-(2-chloropyridin-4-yl)thiazole-5-carboxamide (128mg, 0.351 mmol) and 1,1-dimethoxy-N,N-dimethylmethanamine (0.467 mL,3.51 mmol) in toluene (3.75 mL) was heated at 100° C. for 1 hour. Thereaction was cooled and concentrated in vacuo to give the intermediate,4-(4-chlorobenzyl)-2-(2-chloropyridin-4-yl)-N-((dimethylamino)methylene)thiazole-5-carboxamide,as a solid. LCMS (FA) ES+ 419, 421. The intermediate was dissolved inacetic acid (3.60 mL). Hydrazine hydrate (0.0855 mL, 1.76 mmol) wasadded and the resulting solution was heated at 90° C. for 2 hours. Themixture was cooled and concentrated in vacuo, and the residue wasazeotroped with toluene. The residue was slurried in DCM (30 mL) andsaturated sodium bicarbonate (20 mL). Some undissolved solids werefiltered to give one batch of desired product. The layers of thefiltrate were separated and the aqueous layer was extracted with DCM(2×20 mL). The combined organic layers were dried over MgSO₄, filtered,and concentrated in vacuo to give another batch of desired product. Thetwo product batches were combined and purified by silica gelchromatography (methanol/DCM=0/100→20/80) to give 85 mg of the titlecompound as a beige solid (62% yield). LCMS (FA) ES+ 388, 390. ¹H NMR(300 MHz, d₆-DMSO) δ: 14.48 (bs, 1H), 8.76 (s, 1H), 8.54-8.51 (m, 1H),7.96-7.95 (m, 1H), 7.92-7.89 (m, 1H), 7.38-7.30 (m, 4H), 4.65 (s, 2H).

Example 21 Synthesis ofN-{4-[4-[(4-chlorophenyl)(hydroxy)methyl]-5-(1H-imidazol-2-yl)-1,3-thiazol-2-yl]pyridin-2-yl}acetamide(Compound 60)

Step 1: 2,4-Dibromo-5-(1H-imidazol-2-yl)thiazole

A mixture of 2,4-dibromo-thiazole-5-carbaldehyde (14.8 g, 54.6 mmol),glyoxal trimer dihydrate (22.96 g, 109.2 mmol) and ammonium acetate(25.26 g, 327.8 mmol) in MeOH (450 mL) and acetic acid (31.06 mL) wasstirred at rt overnight. The reaction mixture was concentrated in vacuoto a thick liquid mixture. Remaining acetic acid was removed byazeotroping with toluene (3×100 mL) to afford a dark brown solid. Themixture was purified by column chromatography on silica gel (0 to 25%EtOAc in hexanes) to give pure product (9.12 g, 54%). LCMS: (AA) ES+,310, 312. ¹H NMR (400 MHz, d₆-DMSO) δ: 12.50 (br, 1H), 7.21 (br, 2H).

Step 2:2,4-Dibromo-5-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)thiazole

To a mixture of sodium hydride (2.89 g, 72.2 mmol) in THF (431 mL) wasadded 2,4-dibromo-5-(1H-imidazol-2-yl)thiazole (18.8 g, 60.9 mmol) inTHF (60 mL) at 0° C. After stirring 30 min,2-(trimethylsilyl)ethoxymethyl chloride (11.8 mL, 66.9 mmol) in THF (24mL) was slowly added at 0° C. After 30 min at this temperature, thereaction was quenched by the addition of MeOH (20 mL). The solvent wasevaporated and the residue was purified by column chromatography onsilica gel (0 to 25% EtOAc in hexanes). Product was obtained ascolorless oil (21.8 g, 81.6%). LCMS: (AA) ES+, 440, 442. ¹H NMR (300MHz, CDCl₃) δ: 7.24 (dd, 2H), 5.27 (s, 2H), 3.39 (t, 2H), 0.85 (t, 2H),−0.03 (s, 9H).

Step 3:N-(4-(4-Bromo-5-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)thiazol-2-yl)pyridin-2-yl)acetamide

A mixture of2,4-dibromo-5-(14(2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)thiazole(13.6 g, 31.0 mmol), N-[4-(trimethylstannyl)pyridin-2-yl]acetamide (11.1g, 37.2 mmol), tetrakis(triphenylphosphine)palladium(0) (1.792 g, 1.550mmol), copper(I) iodide (1.77 g, 9.30 mmol) and lithium chloride (3.94g, 93.0 mmol) in 1,4-dioxane (569 mL) was degassed with argon. Themixture was sonicated for 20 min and then heated at 120° C. for 5 h. Thesolvent was evaporated and the crude reaction mixture was purified byISCO chromatography (0 to 3% MeOH in DCM). Product was obtained as anorange solid (10.1 g, 66.0%). LCMS: (AA) ES+, 494, 496. ¹H NMR (300 MHz,CDCl₃) δ: 8.65 (s, 1H), 8.44 (br, 1H), 8.34 (d, 1H), 7.60 (dd, 1H), 7.30(d, 2H), 5.30 (s, 2H), 3.40 (t, 2H), 2.25 (s, 3H), 0.86 (t, 2H), −0.05(s, 9H).

Step 4:N-{4-[5-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl)-4-vinyl-1,3-thiazol-2-yl]pyridin-2-yl}acetamide

N-(4-(4-bromo-5-(14(2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)thiazol-2-yl)pyridin-2-yl)acetamide(0.80 g, 1.6 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.187g, 0.162 mmol) were placed in a microwave vial and sealed underatmosphere of argon. Triethylamine (7.0 mL, 50 mM), THF (7 mL) andtributylethenyl stannane (0.708 mL, 2.43 mmol) were added and themixture was irradiated at 95° C. for 3 hours. The solvent was evaporatedand the residue was purified using column chromatography on silica gel(0 to 60% EA in hexane) to give the title compound (0.65 g, 72%). LCMS:(FA) ES+, 442. ¹H NMR (400 MHz, CDCl₃) δ: 8.80 (s, 1H), 8.41-8.31 (m,1H), 8.09 (s, 1H), 7.70-7.40 (m, 3H), 6.81 (dd, J=17.2, 10.7 Hz, 1H),6.38 (dd, J=17.2, 1.9 Hz, 1H), 5.54 (dd, J=10.7, 1.9 Hz, 1H), 5.27 (s,2H), 3.48-3.34 (m, 2H), 2.25 (s, 3H), 0.90-0.84 (m, 2H), −0.04 (s, 9H).

Step 5:N-{4-[4-formyl-5-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl)-1,3-thiazol-2-yl]pyridin-2-yl}acetamide

N-{4-[5-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl)-4-vinyl-1,3-thiazol-2-yl]pyridin-2-yl}acetamide(0.650 g, 1.47 mmol) was dissolved in tetrahydrofuran (20 mL) and water(10 mL) at ambient temperature and 0.157 M osmium tetraoxide in water(93 uL, 0.014 mmol) was added. The mixture was stirred at roomtemperature for 5 minutes. Sodium metaperiodate (0.661 g, 3.09 mmol) wasthen added in portions over 20 minutes and the mixture was stirred atroom temperature overnight. Solids were removed by filtration and washedwith THF (2×50 mL) and ethyl acetate (2×5 mL). The filtrate wasextracted with ethyl acetate (3×100 mL). The extracts were combined,washed with brine, dried over sodium sulfate, filtered and concentratedunder reduced pressure. Crude material was purified by silica gelchromatography (0 to 30% ethyl acetate in hexanes) to afford the titlecompound (0.25 g, 38%). LCMS: (FA) ES+, 444. ¹H NMR (400 MHz, CDCl₃) δ:8.75 (s, 1H), 10.21 (s, 1H), 8.41 (d, J=5.18 Hz, 1H), 8.20-8.07 (m, 1H),7.76 (dd, J=5.21, 1.58 Hz, 1H), 7.30 (dd, J=2.87, 1.21 Hz, 2H), 5.32 (s,2H), 3.50-3.33 (m, 2H), 2.26 (s, 3H), 0.93-0.78 (m, 2H), −0.04 (s, 9H).

Step 6:N-{4-[4-[(4-chlorophenyl)(hydroxy)methyl]-5-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl)-1,3-thiazol-2-yl]pyridin-2-yl}acetamide

N-{4-[4-formyl-5-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl)-1,3-thiazol-2-yl]pyridin-2-yl}acetamide(0.250 g, 0.564 mmol) was dissolved in tetrahydrofuran (20 mL) andcooled at 0° C. 1.0 M 4-Chlorophenylmagnesium bromide in ether (1.41 mL,1.41 mmol) was added and the solution was stirred at 0° C. for 30minutes. The reaction was quenched by the addition of MeOH (10 mL), andwas evaporated under reduced pressure. The residue was purified usingcolumn chromatography (20 to 100% ethyl acetate in hexane) to give thetitle compound (0.150 g, 48%). LCMS: (FA) ES+, 556, 558. ¹H NMR (400MHz, CDCl₃) δ: 8.69 (s, 1H), 8.34 (d, J=5.23 Hz, 1H), 8.21 (s, 1H), 7.65(dd, J=5.23, 1.55 Hz, 1H), 7.31 (d, J=8.28 Hz, 2H), 7.21-7.16 (m, 3H),7.07 (d, J=1.31 Hz, 1H), 6.26-6.15 (m, 1H), 5.30 (s, 1H), 3.46-3.36 (m,2H), 2.24 (s, 3H), 0.94-0.84 (m, 2H), −0.02 (s, 9H).

Step 7:N-{4-[4-[(4-chlorophenyl)(hydroxy)methyl]-5-(1H-imidazol-2-yl)-1,3-thiazol-2-yl]pyridin-2-yl}acetamide(Compound 60)

N-{4-[4-[(4-chlorophenyl)(hydroxy)methyl]-5-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl)-1,3-thiazol-2-yl]pyridin-2-yl}acetamide(0.120 g, 0.216 mmol) was dissolved in DCM (5 mL) and trifluoroaceticacid (5.0 mL, 65 mmol) was added. The mixture was stirred at roomtemperature overnight. The solvent was evaporated, azeotroped withtoluene and purified using column chromatography on silica gel (0 to 10%MeOH in DCM) to give the title compound (0.050 g, 50%). LCMS: (FA) ES+,426, 428. ¹H NMR (400 MHz, d₄-methanol) δ: 8.68 (s, 1H), 8.38 (d, J=5.24Hz, 1H), 7.64 (dd, J=5.25, 1.60 Hz, 1H), 7.45-7.37 (m, 2H), 7.30-7.23(m, 2H), 7.25-7.09 (m, 2H), 6.37 (s, 1H), 2.20 (s, 3H).

Example 22 Synthesis of3-[4-(4-chlorobenzyl)-5-(4H-1,2,4-triazol-3-yl)-1,3-thiazol-2-yl]-2-methyl-5-(piperazin-1-ylmethyl)pyrazolo[1,5-a]pyridine(Compound 72)

Step 1: 4-(Diethoxymethyl)pyridine

p-Toluenesulfonic acid monohydrate (11.8 g, 62.0 mmol) was dissolved indry ethanol (80 mL) at rt. 4-Pyridinecarboxaldehyde (4.71 mL, 50.0 mmol)was added, followed by ethyl orthoformate (20.79 mL, 125.0 mmol). Themixture was stirred at rt for 17 hours. The mixture was concentrated andthe residue was basified with aqueous saturated NaHCO₃ solution to ˜pH8, extracted with EtOAc (150 mL), washed with brine, dried over Na₂SO₄,filtered, evaporated, and dried under high vacuum to give a liquidproduct. (9.06 g, yield 97.2%). LCMS: (FA) ES⁺ 182. ¹H NMR (400 MHz,CDCl₃) δ: 8.60-8.62 (m, 2H), 7.38-7.40 (m, 2H), 5.50 (s, 1H), 3.53-3.62(m, 4H), 1.23-1.27 (m, 6H).

Step 1A: N-tert-Butoxycarbonyl-O-(mesitylsulfonyl)hydroxylamine

tert-Butyl-N-hydroxycarbamate (5.00 g, 37.6 mmol) and mesitylenesulfonylchloride (8.21 g, 37.6 mmol) were dissolved in 2-methoxy-2-methylpropane(90 mL), flushed with nitrogen and cooled in an ice bath to an internaltemperature of 1° C. Triethylamine (5.34 mL, 38.3 mmol) was addeddropwise over 25 min during which time the temperature increased to 6°C. The mixture was stirred with cooling for 2 hours at which time theinternal reaction temperature was 8° C. The suspension was filtered andthe solids were washed with 2-methoxy-2-methylpropane (60 mL). Thefiltrate was concentrated to −20 mL volume, diluted with hexane (70 mL)and allowed to sit at rt for 30 min. The resulting crystalline solid wascollected by filtration and washed with hexane (20 mL). The motherliquor was evaporated, diluted with hexane (50 mL), and allowed to sit,giving a second crop of crystals. The combined collected solids weredried in vacuum for 1 hour to give a white crystal product (11.06 g,yield 93.4%). LCMS: (AA) ES⁺ 316 and 333 for M⁺+NH₃. ¹H NMR (400 MHz,CDCl₃) δ: 7.54 (s, 1H), 6.99 (s, 2H), 2.68 (s, 6H), 2.32 (s, 3H), 1.31(s, 9H).

Step 2: 1-Amino-4-(diethoxymethyl)pyridinium2,4,6-trimethylbenzenesulfonate

Trifluoroacetic acid (12.0 mL, 156 mmol) was cooled in an ice bath.N-tert butoxycarbonyl-O-(mesitylsulfonyl)hydroxylamine (7.91 g, 25.1mmol) was portionwise added over 15 min. The mixture was stirred withcooling for 2 hours then ˜50 g of ice was added, followed by ˜100 mL ofice water. The resulting white solid was collected by filtration andwashed with water until the washings were ˜pH 6. The solid was dried inair for 15 min to afford a still damp intermediate (6.25 g). The solidthen was dissolved in methylene chloride (160 mL, 2500 mmol), dried overNa₂SO₄, and filtered. The filtrate was cooled in an ice bath and asolution of 4-(diethoxymethyl)pyridine (5.91 g, 32.6 mmol) in drymethylene chloride (20 mL, 300 mmol) was slowly added over 10 min. Theice bath was removed and the mixture was stirred at rt for 50 min. Themixture was concentrated to −30 mL volume. The oily residue wasazeotroped with 15 mL of diethyl ether, then the residue was dilutedwith 250 mL of diethyl ether and cooled in an ice bath for 1 hour, thenstored in a freezer (−20° C.) overnight. An oily residue appeared. Theclear solution was decanted and the oily residue was dried under highvacuum to give a first crop of oily product (2.15 g). The decantedsolution was concentrated to give an oily residue which was trituratedwith hexane (2×100 mL), then dried under high vacuum to give a secondcrop of oily product (6.15 g, yield 79.7% for 2 crops). LCMS: (FA) ES⁺197; ES⁻ 199. ¹H NMR (400 MHz, CDCl₃) δ: 9.00-9.05 (m, 4H), 7.69-7.71(m, 2H), □6.85 (s, 2H), 5.50 (s, 1H), 3.52-3.57 (m, 4H), □2.67 (s, 6H),2.25 (s, 3H), 1.22-1.26 (m, 6H).

Step 3:3-[4-Bromo-5-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,2,4-triazol-3-yl)-1,3-thiazol-2-yl]-5-(diethoxymethyl)-2-methylpyrazolo[1,5-a]pyridine

To a mixture of3-(4-bromo-2-prop-1-yn-1-yl-1,3-thiazol-5-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,2,4-triazole[Prepared as described in Example 14 (4.37 g, 10.9 mmol)] and potassiumcarbonate (3.00 g, 21.7 mmol) in dry N,N-dimethylformamide (20.0 mL) wasadded a solution of 1-amino-4-(diethoxymethyl)pyridinium2,4,6-trimethylbenzenesulfonate (6.37 g, 15.6 mmol) in dryN,N-dimethylformamide (20.0 mL) over 10 min. The resulting dark brownsolution was stirred at rt for 40 hours. The mixture was added to 250 mLof ice water with stirring, then was extracted with EtOAc (100 mL×5)until the aqueous layer turned into a clear solution. The combined EtOAcextracts were washed with water, brine, dried over Na₂SO₄, filtered, andevaporated. The crude product was purified by column chromatography onsilica gel, using EtOAc/hexane (0/100 to 50/50) as an eluant to give asolid product (4.56 g, 70.2%). LCMS: (FA) ES⁺ 593, 595. ¹H NMR (400 MHz,CDCl₃) δ: 8.46 (d, J=2.01 Hz, 1H), 8.40-8.42 (d, J=7.28 Hz, 1H), 8.32(s, 2H), 7.05-7.08 (dd, J=2.01, 7.03 Hz, 1H), □5.57□ (s, 2H □□□3.68-3.77(m, 4H), 3.58-3.63 (m, 2H), 2.75 (s, 3H), 1.28-1.32 (m, 6H), 0.95-1.00(m, 2H), □0.02 (s, 9H)

Step 4:3-[4-(4-Chlorobenzyl)-5-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,2,4-triazol-3-yl)-1,3-thiazol-2-yl]-5-(diethoxymethyl)-2-methylpyrazolo[1,5-a]pyridine

A mixture of3-[4-bromo-5-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,2,4-triazol-3-yl)-1,3-thiazol-2-yl]-5-(diethoxymethyl)-2-methylpyrazolo[1,5-a]pyridine(0.907 g, 1.53 mmol) and bis(tri-t-butylphosphine)palladium(0) (39.0 mg,0.0764 mmol) in a 40 mL vial was evacuated under low vacuum andbackfilled with nitrogen four times. 4-Chlorobenzylzinc chloride intetrahydrofuran (0.50 M, 7.0 mL, 3.5 mmol) was added and the solutionwas again evacuated under low vacuum and backfilled with nitrogen twice.The solution was heated to 60° C. for 4 hours. The reaction mixture wascooled to rt, quenched with water, adjusted to ˜pH 6 with acetic acid,and extracted with EtOAc (2×). The organic layers were combined, washedwith water, brine, dried over Na₂SO₄, filtered and evaporated to give acrude residue which was purified by column chromatography on silica gelcolumn using EtOAc/hexane (0/100 to 40/60) as an eluant to give a solidproduct (0.806 g, 85% pure by ¹H-NMR, yield 70.5%). LCMS: (FA) ES⁺ 639,641. ¹H NMR of pure fraction (400 MHz, CDCl₃) δ: 8.36-8.39 (m, 2H), 8.27(s, 1H), 7.45-7.47 (m, 2H), 7.23-7.25 (m, 2H), 6.99-7.01 (m, 1H), 5.54(s, 2H, 5.50 (s, 1H), 4.67 (s, 2H), 3.66-3.74 (m, 4H), 3.57-3.62 (m,2H), 2.74 (s, 3H), 1.26-1.30 (m, 6H), 0.95-0.99 (m, 2H), 0.00 (s, 9H).

Step 5:3-[4-(4-Chlorobenzyl)-5-(4H-1,2,4-triazol-3-yl)-1,3-thiazol-2-yl]-2-methylpyrazolo[1,5-a]pyridine-5-carbaldehyde

3-[4-(4-Chlorobenzyl)-5-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,2,4-triazol-3-yl)-1,3-thiazol-2-yl]-5-(diethoxymethyl)-2-methylpyrazolo[1,5-a]pyridine(1.17 g, 1.83 mmol) was dissolved in 1,4-dioxane (45 mL) and cooled in awater bath. 12 M hydrochloric acid (15 mL) was added and the mixture wasstirred at rt for 15 hours. Acetic acid (40 mL, 700 mmol) was added andthe suspension was stirred at rt for 24 hours then heated to 70° C. for2 hours, then evaporated. The solid residue was stirred with 1.00hydrochloric acid (100 mL) and methanol (120 mL) at rt for 14 hours. Themixture was evaporated on a rotovap at 45° C. to dryness and thenazeotroped with DCM to give a crude product. The crude product wassuspended in water, basified with NaHCO₃ to pH 8, extracted with EtOAc(300 mL, 3×80 mL), washed with brine, dried over Na₂SO₄, filtered, andevaporated to afford a yellow solid product (0.773 g, yield 97.2%).LCMS: (FA) ES⁺ 435, 437. ¹H NMR (400 MHz, CDCl₃) δ: 10.84 (s, br, 1H),9.99 (s, 1H), 8.75 (m, 1H), 8.43-8.46 (d, J=7.28 Hz, 1H), 8.36 (s, 1H),7.41-7.44 (d, J=8.53 Hz, 2H), 7.32-7.35 (dd, J=7.03, 2.01 Hz, 1H),7.27-7.30 (d, J=8.53 Hz, 2H), 4.69 (s, 2H), 2.79 (s, 3H).

Step 6: tert-Butyl4-({3-[4-(4-chlorobenzyl)-5-(4H-1,2,4-triazol-3-yl)-1,3-thiazol-2-yl]-2-methylpyrazolo[1,5-a]pyridin-5-yl}methyl)piperazine-1-carboxylate

A mixture of3-[4-(4-chlorobenzyl)-5-(4H-1,2,4-triazol-3-yl)-1,3-thiazol-2-yl]-2-methylpyrazolo[1,5-a]pyridine-5-carbaldehyde(0.0563 g, 0.109 mmol), tert-butyl 1-piperazinecarboxylate (60.8 mg,0.326 mmol) and acetic acid (0.0800 mL, 1.41 mmol) in dry methylenechloride (10 mL) was stirred at rt for 15 min. Sodiumtriacetoxyborohydride (69.1 mg, 0.326 mmol) was added and the mixturewas stirred at rt for 15 hours. The mixture was washed with saturatedNaHCO₃ solution and the aqueous layer was extracted with DCM. The DCMextract was washed with water, brine, dried over Na₂SO₄, filtered andevaporated to give a crude product which was purified by columnchromatography on silica gel column using MeOH/DCM (0/100 to 5/95) togive solid product (0.0464 g, yield 70.5%). LCMS: (FA) ES⁺ 605, 607; ES⁻603, 605. ¹H NMR (400 MHz, CDCl₃ and d₄-methanol) δ: 8.23-8.25 (d,J=7.03 Hz, 1H), 8.20 (s, 1H), 7.94 (s, 1H), 7.29-7.31 (d, J=8.28 Hz,2H), 7.15-7.17 (d, J=8.53 Hz, 2H), 6.86-6.89 (dd, J=7.28, 1.76 Hz, 1H),4.53 (s, 2H), 3.45 (s, 2H), 3.33-3.36 (m, 4H), 2.62 (s, 3H), 2.35 (s,br, 4H), 1.37 (s, 9H).

Step 7:3-[4-(4-Chlorobenzyl)-5-(4H-1,2,4-triazol-3-yl)-1,3-thiazol-2-yl]-2-methyl-5-(piperazin-1-ylmethyl)pyrazolo[1,5-a]pyridine(Compound 72)

To a solution of tert-butyl4-({3-[4-(4-chlorobenzyl)-5-(4H-1,2,4-triazol-3-yl)-1,3-thiazol-2-yl]-2-methylpyrazolo[1,5-a]pyridin-5-yl}methyl)piperazine-1-carboxylate(0.0435 g, 0.0719 mmol) in methylene chloride (2.0 mL) and methanol (2.0mL) was added 4 M hydrochloric acid in 1,4-dioxane (2.0 mL, 7.8 mmol).The mixture was stirred at rt for 5 hours then was evaporated,azeotroped with MeOH, and dried under high vacuum to give a solid (˜50mg). The solid was triturated with diethyl ether (10 ml×2) then driedunder high vacuum to give product as a pale yellow powder (0.0424 g,yield 100%) as a bis HCl salt. LCMS: (FA) ES⁺ 505, 507; ES⁻ 503, 505. ¹HNMR (400 MHz, d₄-methanol) δ: 8.71 (s, 1H), 8.62-8.64 (d, J=7.03 Hz,1H), 8.41 (s, 1H), 7.39-7.41 (d, J=8.78 Hz, 2H), 7.27-7.29 (d, J=8.53Hz, 2H), 7.20-7.23 (dd, J=7.03, 2.01 Hz, 1H), 4.66 (s, 2H), 4.38 (s,2H), 3.54 (s, br, 4H), 3.43 (s, br, 4H), 2.73 (s, 3H).

Compounds in the following table were prepared from the appropriatestarting materials in a method analogous to that of Example 22:

31 LCMS: (FA) ES+ 570, 572. 32 LCMS: (FA) ES+ 526, 528. 38 LCMS: (FA)ES+ 493, 495. 54 LCMS: (FA) ES+ 479, 481. 61 LCMS: (FA) ES+ 519, 521. 82LCMS: (FA) ES+ 579, 581. 83 LCMS: (FA) ES+ 569, 571.

Example 23 Synthesis of1-{3-[4-(4-chlorobenzyl)-5-(4H-1,2,4-triazol-3-yl)-1,3-thiazol-2-yl]-2-methylpyrazolo[1,5-a]pyridin-5-yl}methanamine(Compound 1)

Step 1:1-{3-[4-(4-Chlorobenzyl)-5-(4H-1,2,4-triazol-3-yl)-1,3-thiazol-2-yl]-2-methylpyrazolo[1,5-a]pyridin-5-yl}-N-(2,4-dimethoxybenzyl)methanamine

To a suspension of3-[4-(4-chlorobenzyl)-5-(4H-1,2,4-triazol-3-yl)-1,3-thiazol-2-yl]-2-methylpyrazolo[1,5-a]pyridine-5-carbaldehyde(0.300 g, 0.690 mmol) in acetic acid (0.20 mL, 3.5 mmol) and drymethylene chloride (10 mL, 200 mmol) was added 2,4-dimethoxybenzylamine(0.207 mL, 1.38 mmol), followed by additional of sodiumtriacetoxyborohydride (0.363 g, 1.71 mmol). The mixture was stirred atrt. for 16 hours. The mixture was basified with NaHCO₃ solution to pH 8then extracted with DCM. The DCM solution was washed with water. Thecrude product was purified by column chromatography (SiO2, elution with0-100% MeOH in DCM) to afford a solid product (0.252 g, yield 62%).LCMS: (FA) ES⁺ 586, 588; ES⁻ 584, 586. ¹H NMR (400 MHz, CDCl₃ andd₄-methanol) δ: 8.23-8.25 (d, J=7.03 Hz, 1H), 8.18 (s, 1H), 8.01 (s,1H), 7.28-7.30 (d, J=8.53 Hz, 2H), 7.09-7.11 (d, J=8.53 Hz, 2H),7.01-7.03 (d, J=8.28 Hz, 1H), 6.78-6.80 (d, J=7.03 Hz, 1H), 6.33-6.37(m, 2H), 4.53 (s, 2H), 3.65 (s, 2H), 3.64 (s, 6H), 3.61 (s, 2H), 2.61(s, 3H).

Step 2:1-{3-[4-(4-Chlorobenzyl)-5-(4H-1,2,4-triazol-3-yl)-1,3-thiazol-2-yl]-2-methylpyrazolo[1,5-a]pyridin-5-yl}methanamine(Compound 1)

1-{3-[4-(4-chlorobenzyl)-5-(4H-1,2,4-triazol-3-yl)-1,3-thiazol-2-yl]-2-methylpyrazolo[1,5-a]pyridin-5-yl}-N-(2,4-dimethoxybenzyl)methanamine(0.257 g, 0.438 mmol) was dissolved in methylene chloride (6.0 mL) andtrifluoroacetic acid (6.0 mL). Trifluoromethanesulfonic acid (0.050 mL,0.56 mmol) was added and the mixture was heated to 60° C. for 6 days.The mixture was evaporated in a rotary evaporator, azeotroped with EtOAc(3×), and evaporated to give a crude residue. The residue was suspendedin ˜1 mL of MeOH and diluted with 20 mL of Et₂O. The resulting powderwas collected by filtration and dried under high vacuum to afford a palepink solid product. The solid was taken up in EtOAc/water (20 mL/10 mL)and adjusted to ˜pH 8 with NaHCO₃ solution. The layers were separatedand the aqueous layer was extracted with EtOAc (2×30 mL). The combinedEtOAc solutions were washed with water, brine, dried over Na₂SO₄, andfiltered. The filtrate was concentrated to ˜5 mL volume and theprecipitated solid was collected by filtration to give a pure crop ofproduct (0.0069 g). The filtrate was evaporated then dried under highvacuum to afford a second crop of solid product (0.171 g, yield for 2crops 89.9%). LCMS: (FA) ES⁺ 436, 438; ES⁻ 434, 436. ¹H NMR (400 MHz,d₄-methanol) δ: 8.33-8.35 (d, J=7.29 Hz, 1H), 8.24 (s, 1H), 8.09 (s,1H), 7.31-7.33 (d, J=8.78 Hz, 2H), 7.20-7.22 (d, J=8.53 Hz, 2H),6.98-7.00 (m, 1H), 4.59 (s, 2H), 4.06 (s, 2H), 2.67 (s, 3H).

Compound in the following table was prepared from the appropriatestarting materials in a method analogous to that of Example 23:

20 LCMS: (FA) ES+ 586, 588.

Example 24 Synthesis ofN-({3-[4-(4-chlorobenzyl)-5-(4H-1,2,4-triazol-3-yl)-1,3-thiazol-2-yl]-2-methylpyrazolo[1,5-a]pyridin-5-yl}methyl)guanidine(Compound 35)

To a mixture of1-{3-[4-(4-chlorobenzyl)-5-(4H-1,2,4-triazol-3-yl)-1,3-thiazol-2-yl]-2-methylpyrazolo[1,5-a]pyridin-5-yl}methanamine(0.0250 g, 0.0553 mmol) and 1H-pyrazole-1-carboxamidine hydrochloride(8.20 mg, 0.0559 mmol) in dry N,N-dimethylformamide (0.50 mL) was addedN,N-diisopropylethylamine (7.15 mg, 0.0553 mmol). The solution wasstirred at rt for 23 hours. The reaction mixture was diluted with water(15 mL) and extracted with EtOAc (5×15 mL). The EtOAc solution waswashed with brine, dried over Na₂SO₄, filtered, and concentrated in arotary evaporator to give a crude residue. The residue was dissolved in˜0.2 mL of MeOH, then diluted with ˜5 mL of EtOAc. The resulting solidwas collected by filtration to give a pale yellow powder product (0.008g, 30%). LCMS: (FA) ES⁺ 478, 480; ES⁻ 476, 478. ¹H NMR (400 MHz, CDCl₃and d₄-methanol) δ: 8.25-8.27 (d, J=7.28 Hz, 1H), 8.17 (s, 1H), 7.92 (s,1H), 7.21-7.23 (d, J=8.53 Hz, 2H), 7.08-7.10 (d, J=8.28 Hz, 2H),6.72-6.74 (dd, J=7.28, 1.76 Hz, 1H), 4.48 (s, 2H), 4.30 (s, 2H), 2.57(s, 3H).

Example 25 Synthesis ofN-({3-[4-(4-chlorobenzyl)-5-(4H-1,2,4-triazol-3-yl)-1,3-thiazol-2-yl]-2-methylpyrazolo[1,5-a]pyridin-5-yl}methyl)pyrazine-2-carboxamide(Compound 50)

A mixture of1-{3-[4-(4-chlorobenzyl)-5-(4H-1,2,4-triazol-3-yl)-1,3-thiazol-2-yl]-2-methylpyrazolo[1,5-a]pyridin-5-yl}methanamine(0.0222 g, 0.0491), pyrazine-2-carboxylic acid chloride (8.0 mg, 0.056mmol) and N,N-diisopropylethylamine (10 mg, 0.08 mmol) in dry Methylenechloride (5.0 mL) in dry N,N-dimethylformamide (1.0 mL) was sonicatedfor 2 min. The mixture was stirred at rt for 22 hours.N,N-diisopropylethylamine (13 mg, 0.10 mmol) and pyrazine-2-carboxylicacid chloride (9.11 mg, 0.0639 mmol) were added and the mixture wasstirred at rt for 3 days. The mixture was quenched with water, thenextracted with DCM (3×30 mL). The combined DCM solutions were washedwith water, brine, dried over Na₂SO₄, filtered, and evaporated to give acrude product (80 mg). The crude product was purified by HPLC to give asolid product (0.0007 g, yield 3%). LCMS: (AA) ES⁺ 542, 544. ¹H NMR (400MHz, d₆-DMSO) δ: 9.72-9.74 (d, J=6.53 Hz, 1H), 9.23 (s, 1H), 8.87 (s,1H), 8.75 (s, 1H), 8.67-8.69 (d, J=6.53 Hz, 1H), 8.63 (s, 1H), 8.22 (s,1H), 7.24-7.30 (m, 4H), 7.03-7.05 (d, J=7.28 Hz, 1H), 4.62-4.64 (d,J=6.78 Hz, 2H), 4.47 (s, 2H), 2.63 (s, 3H).

Example 26 Synthesis ofN-(2-(2-acetamidopyridin-4-yl)-5-(1H-imidazol-2-yl)thiazol-4-yl)benzamide(Compound 29)

Step 1: 2,4-Dibromo-thiazole-5-carbaldehyde

2,4-Thiazolidinedione (3.50 g, 0.0299 mol) and phosphorus oxybromide(42.76 g, 0.1491 mol) were placed into a two-neck round bottomed flaskand the solid mixture was well mixed. The flask was evacuated and filledwith argon. N,N-dimethylformamide (2.54 mL, 0.0329 mol) was added viasyringe with hand shaking of the flask at the sametime. The mixture wasstirred at rt for 2 hours and then heated slowly to 105° C., until theevolution of hydrogen bromide had ceased, (approximately 4 h). Thereaction was cooled to rt then the mixture was transferred to a beakercontaining 200 g of ice. The aqueous mixture was stirred with DCM thenfiltered. The DCM phase was separated and the aqueous phase wasextracted with DCM twice. The DCM layers were combined and washed withsaturated sodium bicarbonate solution, then brine, dried over anhydroussodium sulfate, filtered and concentrated. The mixture was dry loaded onsilica gel and purified by chromatography to afford2,4-dibromo-thiazole-5-carbaldehyde (2.50 g, 30.9%). LCMS (FA) ES+ 272,274.

Step 2: 2,4-Dibromo-5-(1H-imidazol-2-yl)thiazole

2,4-Dibromo-thiazole-5-carbaldehyde (14.8 g, 54.6 mmol),hexahydro-[1,4]dioxino[2,3-b][1,4]dioxine-2,3,6,7-tetraol (22.96 g,109.2 mmol), and ammonium acetate (25.26 g, 327.8 mmol) were added to around bottomed flask followed by methanol (450 mL, 11000 mmol). Themixture was stirred and acetic acid (31.06 mL, 546.3 mmol) was added.The reaction was stirred overnight then the reaction mixture wasconcentrated under vacuum to provide a thick liquid mixture. Toluene(100 mL) was then added and reevaporated and this process was repeatedseveral times to give a dark brown solid. Methanol was added and themixture was loaded on silica gel. Purification by column chromatographyon silica gel afforded 2,4-dibromo-5-(1H-imidazol-2-yl)thiazole (9.12 g,54%). LCMS (AA) ES+ 310, 312, 308.

Step 3:2,4-Dibromo-5-(14(2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)thiazole

To a mixture of sodium hydride (2.89 g, 72.2 mmol) in tetrahydrofuran(431 mL, 5310 mmol) was added 2,4-dibromo-5-(1H-imidazol-2-yl)thiazole(18.81 g, 60.88 mmol) in tetrahydrofuran (60 mL, 700 mmol) at 0° C. Themixture was stirred for 30 min before [(3-(Trimethylsilyl)ethoxy]methylchloride (11.85 mL, 66.96 mmol) in tetrahydrofuran (24 mL, 3.0E2 mmol)was added slowly at 0° C. The reaction was quenched with MeOH. Thesolvent was evaporated and the residue was purified by columnchromatography on silica gel to afford2,4-dibromo-5-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)thiazole(13.6 g, 81.7%). LCMS (AA) ES+ 440, 442.

Step 4:N-(4-(4-bromo-5-(14(2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)thiazol-2-yl)pyridin-2-yl)acetamide

A mixture of2,4-dibromo-5-(14(2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)thiazole(13.62 g, 31.01 mmol), N-[4-(trimethylstannyl)pyridin-2-yl]acetamide(11.1 g, 37.2 mmol), tetrakis(triphenylphosphine)palladium(0) (1.792 g,1.550 mmol), copper(I) iodide (1.772 g, 9.302 mmol) and lithium chloride(3.944 g, 93.02 mmol) in 1,4-dioxane (569 mL, 7290 mmol) was degassedand filled with argon three times. The mixture was sonicated for 20 minand then heated at 120° C. for 5 h. The reaction mixture was dry loadedonto a silica gel column and purified by chromatography to affordN-(4-(4-bromo-5-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)thiazol-2-yl)pyridin-2-yl)acetamideas an orange solid. LCMS (AA) ES+ 494, 496.

Step 5:N-(2-(2-acetamidopyridin-4-yl)-5-(1H-imidazol-2-yl)thiazol-4-yl)benzamide(Compound 29)

A mixture ofN-(4-(4-bromo-5-(14(2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)thiazol-2-yl)pyridin-2-yl)acetamide(80.9 mg, 0.164 mmol), benzamide (99.1 mg, 0.818 mmol),tris(dibenzylideneacetone)dipalladium(0) (21.3 mg, 0.0233 mmol),4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (39.9 mg, 0.0690 mmol)and cesium carbonate (303 mg, 0.930 mmol) in 1,4-dioxane (7.66 mL, 98.2mmol) was evacuated then filled with argon and then irradiated inmicrowave at 130° C. for 3 h. The reaction mixture was filtered and thefiltrate was purified by column chromatography to afford the desiredintermediate. LCMS (AA) ES+ 535, 536. To the above intermediate wereadded methylene chloride (1.2 mL, 19 mmol) and trifluoroacetic acid (1.8mL, 23 mmol). The mixture was stirred at rt for 2 h. The excesstrifluoroacetic acid and solvent was evaporated and the residue waspurified by HPLC to affordN-(2-(2-acetamidopyridin-4-yl)-5-(1H-imidazol-2-yl)thiazol-4-yl)benzamide(11.3 mg, 17.1%). LCMS (FA) ES+ 406, 407; ¹H NMR (300 MHz, d₄-methanol)δ: 8.67 (d, J=0.45 Hz, 1H), 8.40 (d, J=5.23 Hz, 1H), 8.17-8.07 (m, 2H),7.84-7.78 (m, 1H), 7.59 (dd, J=13.90, 7.27 Hz, 3H), 7.22 (s, 2H), 2.22(s, 3H).

Example 27 Synthesis of4-(2-naphthylmethyl)-2-pyridazin-4-yl-5-(4H-1,2,4-triazol-3-yl)thiophene-3-carbonitrile(Compound 88)

Step 1: Ethyl 3-amino-4,4-dicyano-3-butenoate

Ethyl 3-ethoxy-3-iminopropionate hydrochloride (166 g, 721 mmol.) wassuspended in dry methylene chloride (400 mL, 6000 mmol). Malononitrile(46.7 g, 707 mmol) was added, followed by Triethylamine (1.00 mL, 721mmol). The mixture was heated to reflux for 3 hours. The mixture wascooled to rt then quenched with 200 mL of water. The separated organiclayer was washed with 2×200 mL of water. The combined aqueous layerswere extracted with DCM (3×30 mL). The combined organic layers werewashed with brine, dried over anhydrous Na₂SO₄, filtered, andconcentrated under reduced pressure. The residue was further azeotropedwith MTBE (2×200 mL) and ethyl acetate (70 mL). The residue was dilutedwith 70 mL of EtOAc. A precipitate appeared and the solid was collectedby filtration and washed with ˜20 mL of EtOAc until the pink-red colorof the solid faded to give a first crop of product (32 g). The filtratewas concentrated in rotary evaporator and dried under high vacuum to aweight of ˜110 g. More precipitate appeared after the concentratedfiltrate sat for 1 hour. Approximately 50 mL of Et₂O was added and themixture was allowed to sit overnight. The resulting precipitate wascollected by filtration and washed with Et₂O to afford a second crop ofsolid product (20.59 g). The filtrate was concentrated in a rotaryevaporator to give an oily residue. Chromatography on a silica columnusing EtOAc/hexane (short gradient from 0/100 to 50/50 then stayed on50/50 for 100 min, with 120 mL/min flow rate) afforded a third crop ofpure product (39.3 g, yield for all crops was 72.5%). LCMS: (FA) ES-178.¹H NMR (400 MHz, CDCl₃) δ: 7.57 (s, br, 1H), 6.33 (s, br, 1H),□4.24-4.30 (q, 2H), 3.63 (s, 2H), 1.31-1.35 (t, 3H).

Step 2: Ethyl 3,5-diamino-4-cyanothiophene-2-carboxylate

The mixture of ethyl 3-amino-4,4-dicyano-3-butenoate (91.9 g, 513 mmol)and sulfur (16.4 g, 513 mmol) in dry N,N-dimethylformamide (200 mL, 3000mmol) was cooled in a water bath. Diethylamine (106 mL, 1020 mmol) wasslowly added during which time the internal reaction temperatureincreased to 43° C. The dark-brown solution was then cooled in ice bathto rt (22° C.) then the ice bath was removed. The mixture was stirred atrt for 3 hours. The mixture was poured into ice water (˜1.4 L) and theresulting suspension was allowed to sit overnight. The solid wascollected by filtration and washed with 200 mL of water thoroughly togive a wet solid. The solid was stirred with 1.5 L of EtOAc at rtovernight, then filtered. The filtrate (EtOAc-water bilayer) wasseparated. The solid cake was dissolved in 1.2 L of EtOAc. The combinedEtOAc solutions were washed with brine, dried over anhydrous Na₂SO₄,filtered, rotavaped and dried under high-vacuum overnight to give a drypowder product (102.6 g, yield 94.7%). LCMS: (FA) ES+ 212, ES− 210. ¹HNMR (400 MHz, CDCl₃ and d4-methanol) δ: 4.14 (m, 2H), 1.21-1.25 (t, 3H).

Step 3: Ethyl 3,5-dibromo-4-cyanothiophene-2-carboxylate

Ethyl 3,5-diamino-4-cyanothiophene-2-carboxylate (25.0 g, 118 mmol) wasdissolved in acetonitrile (500 mL, 10000 mmol). Copper(II) Bromide(105.7 g, 473.4 mmol) was added, followed by phosphorus pentoxide (6.72g, 23.7 mmol). The mixture was stirred at room temperature for 30 min,then cooled to 0° C. Butyl nitrite (56.4 mL, 473.4 mmol) was slowlyadded. After the completion of the addition the mixture was heated toreflux for 1 h then cooled to room temperature. The reaction mixture waspoured into 500 mL 4N HCl solution, then extracted with 500 mL DCMtwice. The insoluble material was filtered off from the organic layer.The organic filtrate was dried over MgSO4, and filtered. The filtratewas concentrated and purified by column chromatograph in silica gel,using the eluent of 0-6% ethyl acetate in hexane. The fractionscontaining product were collected and concentrated to give a suspension.The solid was collected by filtration to afford a pure product (14.45 g,yield 36.0%). ¹H NMR (400 MHz, CDCl₃) δ: 4.37-4.42 (q, 2H), 1.38-1.41(t, 3H).

Step 4: 3,5-dibromo-4-cyanothiophene-2-carboxylic acid

Ethyl 3,5-dibromo-4-cyanothiophene-2-carboxylate (6.54 g, 0.0193 mol)was dissolved in a mixture of tetrahydrofuran (40.0 mL, 0.493 mol) andmethanol (20.0 mL, 0.494 mol), then sodium hydroxide in water (1.0 M,60.0 mL, 0.0600 mol) was added at 0° C. The resulting solution waswarmed to rt and stirred for 20 min. The mixture was neutralized withhydrochloric acid in water (4.0 M, 20 mL, 0.080 mol) and extracted with80 mL DCM twice. The combined organic layers were washed with 30 mLwater, evaporated in vacuo to yield a white solid product (5.96 g, yield99.4%). LCMS: (FA) ES−, 307, 309, 311.

Step 5: 3,5-Dibromo-4-cyanothiophene-2-carboxamide

3,5-Dibromo-4-cyanothiophene-2-carboxylic acid (5.90 g, 18.6 mmol) wasadded to a solution of thionyl chloride (27.1 mL, 371 mmol) inacetonitrile (40.0 mL, 766 mmol). The mixture was refluxed for 30 minthen cooled to rt. The solvent was evaporated in vacuo to dryness toyield a lightly yellow solid. Methylene chloride (100 mL, 2000 mmol) wasadded to dissolve the solid, then the solution was cooled to 0° C. Undera nitrogen atmosphere, a solution of 0.500 M ammonia in 1,4-dioxane(111.5 mL, 55.7 mmol) was slowly added, and the mixture was brought toroom temperature for 1 h. The mixture was evaporated in vacuo to give asolid residue. 100 mL of 1N HCl was added and the suspension was stirredfor 1 h at room temperature. The solid product was collected byfiltration and dried under high vacuum to give product (5.64 g, yield98%). LCMS: (FA) ES−, 308, 310, 312.

Step 6: 2,4-Dibromo-5-(4H-1,2,4-triazol-3-yl)thiophene-3-carbonitrile

3,5-Dibromo-4-cyanothiophene-2-carboxamide (5.90 g, 19.0 mmol) wassuspended in dry Toluene (250 mL, 2300 mmol).1,1-Dimethoxy-N,N-dimethylmethanamine (10.1 mL, 76.1 mmol) was added andthe mixture was heated to 90° C. for 1 hour. The mixture was cooled tort then rotavaped to dryness to give a crude intermediate. Theintermediate was suspended in acetic acid (150 mL, 2600 mmol). Hydrazinehydrate (5.78 mL, 76.1 mmol) was added dropwise and the temperature wasraised to 55° C. The mixture was stirred at the same temperature for 2hours. The suspension was then evaporated to remove most of acetic acid.The resulting solid was collected by filtration and dried under vacuumto give a product (5.54 g, yield 87.2%). LCMS: (FA) ES−, 331, 333, 335.¹H NMR (300 MHz, d6-dmso) δ: 14.2 (s, br, 1H), 8.65 (s, 1H).

Step 7:2,4-Dibromo-5-[1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl]thiophene-3-carbonitrile

2,4-Dibromo-5-(4H-1,2,4-triazol-3-yl)thiophene-3-carbonitrile (0.80 g,2.4 mmol) was placed in a 500 mL round bottom flask and tetrahydrofuran(50 mL, 600 mmol) was added. To the resulting solution were addeddihydropyran (1.31 mL, 14.4 mmol) and p-toluenesulfonic acid monohydrate(0.683 g, 3.59 mmol). The mixture was stirred for 3 h at rt. Thesolution was then poured into 20 mL water and extracted with 40 mL ethylacetate twice. The combined organic layers were evaporated in vacuo. Theresidue was purified by column chromatography using 0-35% EtOAc inhexane to afford a solid product (0.842 g, yield 84%). LCMS: (AA) ES+,417, 419, 421. ¹H NMR (300 MHz, CDCl₃) δ: 8.38 (s, 1H), 5.55-5.60 (m,1H), 4.06-4.10 (m, 1H), 3.68-3.78 (m, 1H), 2.15-2.28 (m, 1H), 2.01-2.13(m, 2H), 1.66-1.80 (m, 3H).

Step 8:4-Bromo-2-pyridazin-4-yl-5-[1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl]thiophene-3-carbonitrile

A mixture of2,4-dibromo-5-[1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl]thiophene-3-carbonitrile(0.248 g, 0.594 mmol), 4-(tributylstannyl)pyridazine (2.30 mg, 0.624mmol), copper(I) iodide (34.0 mg, 0.178 mmol), lithium chloride (75.6mg, 1.78 mmol) and tetrakis(triphenylphosphine)palladium(0) (34.3 mg,0.0297 mmol) in dry 1,4-dioxane (5.0 mL, 64 mmol) was sonicated under anitrogen atmosphere for 2 min then heated in a capped vial to 130° C. inmicrowave machine for 20 mins. The suspension was cooled to rt, dilutedwith 20% MeOH/DCM (˜100 mL), treated with 12 g of silica gel thenrotavaped and dried under high vacuum. The coated silica gel waschromatographed on a silica column eluting with MeOH/DCM (0/100 to 5/95)to afford a solid product (0.143 g, yield 57.7%). LCMS: (AA) ES+, 417,419. ¹H NMR (300 MHz, CDCl₃) δ: 9.55 (s, 1H), 9.37-9.39 (m, 1H), 8.40(s, 1H), 7.69-8.00 (m, 1H), 5.55-5.60 (m, 1H), 4.08-4.13 (m, 1H),3.73-3.81 (m, 1H), 2.18-2.30 (m, 1H), 2.03-2.16 (m, 2H), 1.68-1.82 (m,3H).

Step 9:4-(2-Naphthylmethyl)-2-pyridazin-4-yl-5-[1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl]thiophene-3-carbonitrile

Bis(tri-t-butylphosphine)palladium(0) (4.92 mg, 0.00963 mmol),4-bromo-2-pyridazin-4-yl-5-[1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl]thiophene-3-carbonitrile(0.0402 g, 0.0963 mmol), 2-naphthylmethylzinc bromide in tetrahydrofuran(0.50M, 0.578 mL, 0.289 mmol) and tetrahydrofuran (4.0 mL, 49 mmol) wereadded to a microwave tube. The tube was sealed under a nitrogenatmosphere and heated at 70° C. for 2 h then cooled to rt. The mixturewas concentrated in vacuo and the residue was purified by chromatographyon a silica gel column eluting with 0-100% EtOAc in hexane to afford asolid product (0.0332 g, yield 72%). LCMS: (AA) ES+, 479. ¹H NMR (300MHz, d4-methanol) δ: 9.63 (s, 1H), 9.28-9.35 (m, 1H), 8.68 (s, 1H),8.13-8.15 (m, 1H), 7.69-8.00 (m, 4H), 7.37-7.48 (m, 3H), 5.62-5.66 (m,1H), 3.94-4.08 (m, 1H), 3.69-3.80 (m, 1H), 3.30 (s, 2H), 2.07-2.22 (m,1H), 1.95-2.07 (m, 2H), 1.61-1.79 (m, 3H).

Step 10:4-(2-naphthylmethyl)-2-pyridazin-4-yl-5-(4H-1,2,4-triazol-3-yl)thiophene-3-carbonitrile(Compound 88)

4-(2-Naphthylmethyl)-2-pyridazin-4-yl-5-[1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl]thiophene-3-carbonitrile(0.03178 g, 0.06641 mmol) was dissolved in methanol (3.00 mL, 74.0mmol). HCl in water (12 M, 3.00 mL, 36.0 mmol) was added. The solutionwas heated at 50° C. for 60 min then cooled to rt. The mixture wasevaporated in vacuo to remove the most of methanol. To the residue wasadded 30 mL saturated sodium bicarbonate solution, extracted with 40 mLethyl acetate twice. The combined EtOAc layers were washed with 20 mLwater then concentrated in vacuo. The resulting crystalline solid wascollected by filtration to afford a pure product (0.0158 g, yield60.3%). LCMS: (AA) ES+ 395. ¹H NMR (300 MHz, d4-methanol) δ: 9.60 (s,1H), 9.27-9.29 (m, 1H), 8.47 (s, 1H), 8.09-8.11 (m, 1H), 7.69-7.77 (m,4H), 7.37-7.47 (m, 3H), 3.30 (s, 2H).

The compound in the following table was prepared from the appropriatestarting materials in a method analogous to that of Example 27:

89 LCMS: (FA) ES+ 379, 381.

Example 28 Synthesis of4-(4-chlorobenzyl)-2-morpholinothiazole-5-carboxylic acid (Compound 91)

Step 1, Preparation of ethyl4-(4-chlorobenzyl)-2-morpholinothiazole-5-carboxylate

To a solution of ethyl 2-bromo-4-(4-chlorobenzyl)thiazole-5-carboxylate(4.19 g, 11.6 mmol, prepared as described in Example 10) inN-methylpyrrolidinone (12.2 mL) was added potassium carbonate (3.21 g,23.2 mmol) and morpholine (1.52 mL, 17.4 mmol) and the resulting mixturewas heated to 130 degrees for 90 minutes. The reaction was cooled andthe volatiles were removed by concentration at 65 degrees under oil pumpvacuum. The residue was taken up in DCM (100 mL) and water (50 mL). Thelayers were separated and the aqueous layer was extracted with DCM (50mL). The combined DCM layers were dried over MgSO₄, filtered, andconcentrated to give the crude product, which was purified by silica gelchromatography (ethyl acetate/hexane=0/100→35/65) to give 3.44 g of thetitle compound as a white solid. (80% yield). LCMS (FA) ES+ 367. ¹H NMR(300 MHz, CDCl₃) δ: 7.32-7.27 (m, 2H), 7.24-7.20 (m, 2H), 4.28 (s, 2H),4.27 (q, 2H, J=7.2 Hz), 3.80-3.76 (m, 4H), 3.53-3.48 (m, 4H), 1.32 (t,3H, J=7.2 Hz).

Step 2, Preparation of4-(4-chlorobenzyl)-2-morpholinothiazole-5-carboxylic acid. (Compound 91)

To a solution of ethyl4-(4-chlorobenzyl)-2-morpholinothiazole-5-carboxylate (3.44 g, 9.38mmol) in THF (53 mL) was added water (26 mL) and 1 N LiOH (28.2 mL, 28.2mmol) and the resulting mixture was heated to 40 degrees overnight. Thereaction was cooled, acidified with 1 N HCl, and extracted with ethylacetate (3×50 mL). The combined ethyl acetate layers were dried overMgSO₄, filtered, and concentrated to give the crude product, which waspurified by silica gel chromatography (methanol/DCM=0/100→20/80).Recrystallization from ethyl acetate/hexanes gave 1.3 g of the titlecompound as a white solid. (41% yield). LCMS (FA) ES+ 339. ¹H NMR (400MHz, DMSO-d₆) δ: 12.74 (s, 1H), 7.33-7.30 (m, 2H), 7.26-7.23 (m, 2H),4.21 (s, 2H), 3.67-3.64 (m, 4H), 3.42-3.40 (m, 4H).

Example 29 Synthesis of2-(4-(4-chlorobenzyl)-2-(pyridin-4-yl)thiazol-5-yl)pyrimidin-4(3H)-one(Compound 92)

Step 1, Preparation of4-(4-chlorobenzyl)-2-(pyridin-4-yl)thiazole-5-carboximidamidehydrochloride

To a suspension of ammonium chloride (2.25 g, 42.1 mmol) in toluene(21.0 mL) in an ice bath was added 2.0 M trimethylaluminum in toluene(21.1 mL, 42.2 mmol) dropwise (gas evolution). The mixture was thenstirred at room temperature for 30 minutes, during which time the solidsdissolved. Ethyl 4-(4-chlorobenzyl)-2-morpholinothiazole-5-carboxylate(4.11 g, 11.4 mmol) was added in one portion and the resulting solutionwas heated slowly to 110° C. over 1 hour, then kept at 110° C. for 2.5hours. The reaction was allowed to cool to room temperature overnight.The reaction was poured into a slurry of silica gel (10 grams) inchloroform (100 mL) and stirred 10 minutes. Methanol (20 mL) was added(bubbling occurs), and the mixture was filtered through a short silicagel bed in a sintered glass funnel, eluting with 1:1 methanol/chloroformto remove product. The filtrate was concentrated to give the crudeproduct, which was purified by silica gel chromatography(methanol/chloroform=50/50) to give 1.9 g of the title compound as alight yellow solid, which is the HCl salt. (45% yield). (1.6 grams (45%)of 4-(4-chlorobenzyl)-2-(pyridin-4-yl)thiazole-5-carbonitrile was alsorecovered) LCMS (FA) ES+ 329. ¹H NMR (400 MHz, DMSO-d₆) δ: 9.73, (bs,4H), 8.76-8.74 (m, 2H), 7.90-7.88 (m, 2H), 7.39-7.35 (m, 2H), 7.31-7.27(m, 2H), 4.30 (s, 2H).

Step 2, Preparation of2-(4-(4-chlorobenzyl)-2-(pyridin-4-yl)thiazol-5-yl)pyrimidin-4(3H)-one(Compound 92)

To a solution of4-(4-chlorobenzyl)-2-(pyridin-4-yl)thiazole-5-carboximidamidehydrochloride (188 mg, 0.515 mmol) in ethanol (8.0 mL) was added 21%sodium ethoxide in ethanol (0.192 mL, 0.515 mmol) and sodium2-ethoxycarbonyl ethenolate (284 mg, 2.06 mmol) (prepared as in J. Med.Chem., (2001), 44(17), 2695-2700), and the reaction was heated to refluxovernight. The reaction was cooled and concentrated. The residue wasslurried DCM (15 mL) and water (15 mL) for 20 minutes. The solids werefiltered, dried and purified by silica gel chromatography(methanol/DCM=0/100→15/85) to give the product. HPLC gave 23 mg of thetitle compound as a yellow solid. (12% yield). LC/MS (FA) ES+ 381. ¹HNMR (300 MHz, DMSO-d₆) δ: 8.72-8.60 (m, 2H), 8.41 (d, 1H, J=5.7 Hz),7.88-7.85 (m, 2H), 7.40-7.36 (m, 2H), 7.32-7.28 (m, 2H), 6.58 (d, 1H,J=5.7 Hz), 4.80 (s, 2H).

Example 30 Synthesis ofN-{4-[4-{(4-chlorophenyl)[3-(dimethylamino)azetidin-1-yl]methyl}-5-(4H-1,2,4-triazol-3-yl)-2-thienyl]pyridin-2-yl}acetamide(Compound 181)

Step 1: Preparation ofN-{4-[4-[(4-chlorophenyl)(hydroxy)methyl]-5-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,2,4-triazol-3-yl)-2-thienyl]pyridin-2-yl}acetamid

A mixture of[5-bromo-2-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,2,4-triazol-3-yl)-3-thienyl](4-chlorophenyl)methanol(3.07 g, 5.52 mmol)) (synthesized in an analogous way as described inExample 2), N-[4-(trimethylstannyl)pyridin-2-yl]acetamide (1.81 g, 6.07mmol), tetrakis(triphenylphosphine)palladium(0) (319 mg, 0.28 mmol),copper(I) iodide (315 mg, 1.65 mmol) and lithium chloride (702 mg, 16.5mmol) in 1,4-dioxane (25.0 mL) was stirred at 100° C. for 2 hours underan atmosphere of nitrogen. The reaction was cooled to room temperatureand concentrated with Celite. The crude mixture was purified by columnchromatography (SiO₂, eluent with methanol in dichloromethane, 0-5%gradient) to afford a yellow solid (2.48 g, 80%). LCMS: (AA) ES+ 556,558; ¹H NMR (400 MHz, CDCl₃) δ: 8.48 (br s, 1H), 8.43 (br s, 1H), 8.25(s, 1H), 8.19 (d, J=5.6 Hz, 1H), 7.41 (d, J=8.4 Hz, 2H), 7.33-7.24 (m,2H), 7.19 (s, 1H), 7.16 (dd, J=1.2, 5.6 Hz, 1H), 6.22 (s, 1H), 6.05 (brs, 1H), 5.51 (s, 2H), 3.66 (t, J=8.4 Hz, 2H), 2.22 (s, 3H), 0.94 (t,J=8.4 Hz, 2H), −0.01 (s, 9H).

Step 2: Preparation ofN-{4-[4-{(4-chlorophenyl)[3-(dimethylamino)azetidin-1-yl]methyl}-5-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,2,4-triazol-3-yl)-2-thienyl]pyridin-2-yl}acetamide

To a solution ofN-{4-[4-[(4-chlorophenyl)(hydroxy)methyl]-5-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,2,4-triazol-3-yl)-2-thienyl]pyridin-2-yl}acetamide(100 mg, 0.18 mmol) in dichloromethane (2.00 mL) was added phosphoruspentachloride (112 mg, 0.54 mmol) at room temperature. The mixture wasstirred for 15 min and then water (10 mL) was added. The mixture wasstirred vigorously for 10 min. The layers were separated and the aqueouslayer was extracted with dichloromethane twice. The combined organiclayers were washed with saturated NaHCO₃ solution, dried over Na₂SO₄,filtered, and concentrated in vacuo to give an intermediate as a yellowsolid. This intermediate was dissolved in acetonitrile (1.66 mL) andpotassium carbonate (124 mg, 0.90 mmol) and1-azetidin-3-yl-dimethylamine hydrochloride (130 mg, 0.54 mmol) wereadded. The mixture was stirred at 80° C. for 5 hours. After cooling toroom temperature, the mixture was diluted with dichloromethane andfiltered through a glass filter. The filtrate was concentrated in vacuoand the residue was purified by column chromatography (SiO₂, elutionwith methanol in dichloromethane, 0-10% gradient) to afford a solidproduct (103 mg, 52.3%). LCMS: (AA) ES+ 638, 640; ¹H NMR (400 MHz,CDCl₃) δ: 8.48 (s, 1H), 8.26 (s, 1H), 8.22 (d, J=5.2 Hz, 1H), 8.10 (s,1H), 7.80 (s, 1H), 7.62 (d, J=8.4 Hz, 2H), 7.25-7.21 (m 3H), 5.61 (s,1H), 5.56 (s, 2H), 3.72 (dd, J=8.8, 7.6 Hz, 2H), 3.43-3.32 (m, 2H),2.93-2.80 (m, 3H), 2.24 (s, 3H), 2.06 (s, 6H), 0.99 (dd, J=8.8, 7.6 Hz,2H), 0.02 (s, 9H).

Step 3: Preparation ofN-{4-[4-{(4-chlorophenyl)[3-(dimethylamino)azetidin-1-yl]methyl}-5-(4H-1,2,4-triazol-3-yl)-2-thienyl]pyridin-2-yl}acetamide(Compound 181)

N-{4-[4-{(4-chlorophenyl)[3-(dimethylamino)azetidin-1-yl]methyl}-5-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,2,4-triazol-3-yl)-2-thienyl]pyridin-2-yl}acetamide(60 mg, 0.094 mmol) was dissolved in dichloromethane (1.19 mL) andtrifluoroacetic acid (0.30 mL, 3.85 mmol) was added. The mixture wasstirred at room temperature overnight. The mixture was concentrated invacuo and distributed between EtOAc and saturated NaHCO₃ solution. Theaqueous layer was extracted with EtOAc twice. The combined organiclayers were dried over Na₂SO₄, filtered, and concentrated. The residuewas purified by column chromatography (SiO₂, elution with methanol indichloromethane, 0-20% gradient) to afford the title compound as a whitesolid (34.2 mg, 71.6%). LCMS: (AA) ES+ 508, 510; ¹H NMR (400 MHz,d₄-methanol): 8.51 (s, 1H), 8.39 (s, 1H), 8.24 (br s, 1H), 7.78 (s, 1H),7.59 (d, J=8.4 Hz, 2H), 7.32 (br s, 1H), 7.26 (d, J=8.4 Hz, 2H), 5.71(s, 1H), 3.45-3.36 (m, 2H), 3.00-2.83 (m, 3H), 2.19 (s, 3H), 2.06 (s,6H).

The compounds in the following table were prepared from the appropriatestarting materials in a method analogous to that of Example 30:

129 LCMS: (AA) ES+ 494, 496. 144 LCMS: (AA) ES+ 508, 510. 157 LCMS: (AA)ES+ 576, 578. 160 LCMS: (AA) ES+ 508, 510. 170 LCMS: (AA) ES+ 494, 496.172 LCMS: (AA) ES+ 479. 189 LCMS: (AA) ES+ 450, 452. 211 LCMS: (AA) ES+451, 453. 218 LCMS: (AA) ES+ 519, 521. 222 LCMS: (AA) ES+ 522, 524. 223LCMS: (AA) ES+ 509, 511. 226 LCMS: (AA) ES+ 469, 471. 227 LCMS: (AA) ES+463, 465. 230 LCMS: (AA) ES+ 479, 481. 244 LCMS: (FA) ES+ 467, 469. 245LCMS: (AA) ES+ 536, 538. 250 LCMS: (AA) ES+ 408, 410. 269 LCMS: (AA) ES+509, 511. 274 LCMS: (AA) ES+ 494, 496. 277 LCMS: (AA) ES+ 494, 496.

Example 31 Synthesis ofN-(4-{4-[(4-chlorophenyl)(hydroxy)(1-methylpiperidin-4-yl)methyl]-5-(4H-1,2,4-triazol-3-yl)-2-thienyl}pyridin-2-yl)acetamide(Compound 237)

Step 1: A solution of oxalyl chloride (63.1 uL, 0.746 mmol) in methylenechloride (1.50 mL, 23.4 mmol) was cooled to −78° C. To this solution wasadded dimethyl sulfoxide (65.1 uL, 0.918 mmol) in methylene chloride(1.00 mL) dropwise. The reaction was stirred for 10 min under anatmosphere of Nitrogen. To this mixture was added a solution ofN-{4-[4-[(4-chlorophenyl)(hydroxy)methyl]-5-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,2,4-triazol-3-yl)-2-thienyl]pyridin-2-yl}acetamide(319 mg, 0.574 mmol) in methylene chloride (1.50 mL) dropwise. In 1 hr,triethylamine (0.400 mL, 2.87 mmol) was added dropwise to the reactionand the resulting mixture was warmed to rt. In 1 hr, the solution wasdiluted with CH₂Cl₂ and washed with water. The aqueous layer wasextracted with CH₂Cl₂(×2). The combined org layer was washed withNaHCO₃(aq) saturated solution, dried, and concentrated to provideN-{4-[4-(4-chlorobenzoyl)-5-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,2,4-triazol-3-yl)-2-thienyl]pyridin-2-yl}acetamideas a yellow solid (325 mg, quantative). LCMS: (AA) 554, 556; ¹H NMR (400MHz, CDCl₃) δ 8.56-8.47 (s, 1H), 8.32-8.24 (m, 1H), 8.11-8.03 (s, 1H),8.03-7.92 (s, 1H), 7.87-7.77 (m, 2H), 7.63-7.57 (s, 1H), 7.42-7.32 (m,3H), 5.37-5.32 (s, 2H), 3.53-3.40 (t, J=8.1 Hz, 2H), 2.27-2.19 (s, 3H),0.94-0.80 (t, J=8.1 Hz, 2H), 0.02-−0.04 (s, 9H).

Step 2: A 25 mL round bottom flask charged with magnesium turnings (23.0mg, 0.947 mmol) was flame-dried. To the flask was added tetrahydrofuran(1.00 mL) and a drop of 1,2-dibromoethane. The mixture was heated to 45°C. for 10 min and cooled to rt. To the mixture was added4-chloro-N-methylpiperidine (126 mg, 0.947 mmol). The reaction wasstirred at 35° C. under an atmosphere of nitrogen for 12 hrs. Themixture turned cloudy, and magnesium turnings eventually disappeared, asthe reaction progressed. To a solution ofN-{4-[4-(4-chlorobenzoyl)-5-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,2,4-triazol-3-yl)-2-thienyl]pyridin-2-yl}acetamide(113 mg, 0.204 mmol) in tetrahydrofuran (1.00 mL) was added thepre-prepared Grignard reagent solution dropwise at 0° C. In 3 hrs, thereaction was warmed to rt. In another 3 hrs, the reaction was quenchedwith water and distributed between NaHCO₃(aq) saturated solution andEtOAc. The aqueous layer was extracted with EtOAc (×2). The combinedorganic layer was dried and concentrated. Purification on a silica gelcolumn (gradient elution, 1-20% MeOH) providedN-(4-{4-[(4-chlorophenyl)(hydroxy)(1-methylpiperidin-4-yl)methyl]-5-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,2,4-triazol-3-yl)-2-thienyl}pyridin-2-yl)acetamideas a yellow solid (59.0 mg, 44.3% yield). LCMS: (AA) ES+ 653, 655; ¹HNMR (400 MHz, CDCl₃) δ 8.77-8.66 (s, 1H), 8.60-8.49 (s, 1H), 8.31-8.23(d, J=5.3 Hz, 1H), 8.15-8.08 (m, 2H), 7.66-7.60 (s, 1H), 7.34-7.23 (m,3H), 7.17-7.08 (d, J=8.7 Hz, 2H), 5.45-5.38 (s, 2H), 3.63-3.51 (m, 2H),3.49-3.44 (s, 3H), 3.02-2.90 (d, J=10.8 Hz, 1H), 2.90-2.78 (d, J=11.2Hz, 1H), 2.28-2.20 (m, 4H), 2.20-2.09 (m, 1H), 2.07-1.95 (m, 1H),1.96-1.78 (m, 2H), 1.76-1.58 (qd, J=12.7, 3.8 Hz, 1H), 1.16-1.07 (d,J=12.5 Hz, 1H), 0.99-0.85 (m, 2H), 0.02-−0.04 (s, 9H).

Step 3: A 5 mL microwave tube was charged withN-(4-{4-[(4-chlorophenyl)(hydroxy)(1-methylpiperidin-4-yl)methyl]-5-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,2,4-triazol-3-yl)-2-thienyl}pyridin-2-yl)acetamide(10.0 mg, 0.0153 mmol) and tetrahydrofuran (0.500 mL, 6.16 mmol). To thesolution was added 1.00 M of tetra-n-butylammonium fluoride intetrahydrofuran (61.2 uL). The tube was sealed and heated to 80° C. inan oil bath for 4 hrs. The resulting mixture was cooled to rt anddistributed between NaHCO₃(aq) saturated solution and EtOAc. The aqueouslayer was extracted with EtOAc (×2). The combined org layer was driedand concentrated. Purification on HPLC (reverse phase, AA) providedN-(4-{4-[(4-chlorophenyl)(hydroxy)(1-methylpiperidin-4-yl)methyl]-5-(4H-1,2,4-triazol-3-yl)-2-thienyl}pyridin-2-yl)acetamideas a white solid. (2.0 mg, 25% yield) LCMS (AA) ES+ 523, 525; ¹H NMR(400 MHz, MeOD) δ 8.50-8.42 (s, 1H), 8.41-8.36 (s, 1H), 8.36-8.29 (d,J=5.3 Hz, 1H), 7.92-7.83 (s, 1H), 7.50-7.43 (m, 1H), 7.43-7.34 (d, J=8.6Hz, 2H), 7.25-7.14 (d, J=8.6 Hz, 2H), 2.91-2.76 (m, 1H), 2.65-2.55 (m,4H), 2.26-2.15 (s, 3H), 2.11-2.01 (m, 2H), 1.88-1.72 (m, 2H), 1.70-1.57(s, 1H), 1.47-1.35 (dd, J=15.0, 7.4 Hz, 1H), 1.31-1.20 (m, 2H).

The compounds in the following table were prepared from the appropriatestarting materials in a method analogous to that of Example 31:

145 LCMS: (AA) ES+ 511, 513 225 LCMS: (AA) ES+ 493, 495. 273 LCMS: (AA)ES+ 508, 510.

Example 32 Synthesis of4-(4-(4-chlorobenzyl)-2-(pyridin-4-yl)thiazol-5-yl)pyrimidin-2-amine(Compound 150)

Step 1, Preparation of1-(4-(4-chlorobenzyl)-2-(pyridin-4-yl)thiazol-5-yl)ethanone

To a solution of4-(4-chlorobenzyl)-N-methoxy-N-methyl-2-(pyridin-4-yl)thiazole-5-carboxamide(1.79 g, 4.79 mmol) in THF (97 mL) at −20° C. was added a 1.60 Msolution of MeLi in ether (4.19 mL, 6.70 mmol). The reaction was stirredfor 30 minutes at −20° C. An additional portion of a 1.60 M solution ofMeLi in ether (0.838 mL, 1.34 mmol) was added and the reaction wasstirred for 30 more minutes at −20° C. The reaction was quenched byadding saturated ammonium chloride (25 mL) followed by water (35 mL).The mixture was extracted with ethyl acetate (2×150 mL) and the combinedorganic layers were dried, filtered and concentrated in vacuo. Theresidue was purified by silica gel chromatography (EA/DCM=0/100→80/20)to give 1.27 g (81% yield) of the title compound. as a light yellowsolid. LCMS (FA) ES+ 329, 331. ¹H NMR (300 MHz, CDCl₃) δ: 8.75-8.73 (m,2H), 7.83-7.81 (m, 2H), 7.34-7.31 (m, 2H). 7.26-7.23 (m, 2H), 4.53 (s,2H), 2.59 (s, 3H).

Step 2, Preparation of(E)-1-(4-(4-chlorobenzyl)-2-(pyridin-4-yl)thiazol-5-yl)-3-(dimethylamino)prop-2-en-1-one

A solution of1-(4-(4-chlorobenzyl)-2-(pyridin-4-yl)thiazol-5-yl)ethanone (370 mg,1.12 mmol) in 1,1-dimethoxy-N,N-dimethylmethanamine (10.0 mL, 75.3 mmol)was heated to 80 degrees for 6 hours. The reaction was cooled andconcentrated in vacuo. The residue was purified by silica gelchromatography (EA DCM=0/100→100/0) to give 389 mg (90% yield) of thetitle compound. as a yellow solid. LCMS (FA) ES+ 384, 386. ¹H NMR (300MHz, CDCl₃) δ: 8.70-8.68 (m, 2H), 7.81-7.75 (m, 3H), 7.36-7.33 (m, 2H),7.26-7.24 (m, 2H), 5.41 (d, 1H, J=12.3 Hz), 4.55 (s, 2H), 3.16 (s, 3H),2.88 (s, 3H).

Step 3, Preparation of4-(4-(4-chlorobenzyl)-2-(pyridin-4-yl)thiazol-5-yl)pyrimidin-2-amine

To a solution of(E)-1-(4-(4-chlorobenzyl)-2-(pyridin-4-yl)thiazol-5-yl)-3-(dimethylamino)prop-2-en-1-one(93.0 mg, 0.242 mmol) in isopropyl alcohol (1.0 mL) was added guanidinehydrochloride (34.7 mg, 0.363 mmol) and sodium ethoxide (65.4 mg, 1.21mmol) and the resulting mixture was heated to reflux for 3 days. Thereaction was cooled and concentrated in vacuo. The residue was slurriedin DCM (10 mL) and water (10 mL). The undissolved solids were filtered.This material was purified by preparative reverse phase chromatographyto give 57 mg (62% yield) of the title compound as a white solid. LCMS(FA) ES+ 380, 382. ¹H NMR (300 MHz, DMSO-d₆) δ 8.73-8.71 (m, 2H), 8.31(d, 1H, J=5.1 Hz), 7.88-7.86 (m, 2H), 7.36-7.30 (m, 4H), 6.86 (bs, 2H),6.84 (d, 1H, J=5.1 Hz), 4.56 (s, 2H).

Example 33 Synthesis of Methyl{4-[4-[(4-chlorophenyl)(hydroxy)methyl]-3-cyano-5-(4H-1,2,4-triazol-3-yl)-2-thienyl]pyridin-2-yl}carbamate(Compound 195)

Step 1: Methyl(4-{4-bromo-3-cyano-5-[1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl]-2-thienyl}pyridin-2-yl)carbamate

A mixture of2,4-dibromo-5-[1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl]thiophene-3-carbonitrile(1.27 g, 3.05 mmol), methyl[4-(trimethylstannyl)pyridin-2-yl]carbamate(0.960 g, 3.05 mmol), lithium chloride (0.388 g, 9.14 mmol), copper(I)iodide (0.174 g, 0.914 mmol) and tetrakis(triphenylphosphine)platinum(0) (0.190 g, 0.152 mmol) in anhydrous 1,4-dioxane (45 mL) was degassedby evacuation in vacuum and backfilling with N₂ 4 times, then heated to100° C. under N₂ for 8 hours, then cooled to room temperature. Thesuspension was filtered and washed with dioxane. The solid was suspendedin 20% MeOH in DCM (300 mL), and washed with water (2×). The organicsuspension was concentrated in a rotavapor to give a solid residue. Theresidue was stirred in DMF/DCM (10 mL/10 mL) at room temperature for 20min, filtered and washed with DCM to give a solid product (1.16 g, yield77.8%). LCMS: (FA) ES+ 489, 491. ¹H NMR (400 MHz, d₄-MeOH/d-chloroform)δ 8.26-8.35 (m, 3H), 7.34 (m, 1H), 5.48 (m, 1H), 4.00 (m, 1H), 3.73 (s,3H), 3.64-3.69 (m, 1H), 1.97-2.14 (m, 3H), 1.58-1.68 (m, 3H).

Step 2: Methyl(4-{3-cyano-5-[1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl]-4-vinyl-2-thienyl}pyridin-2-yl)carbamate

A mixture of methyl(4-{4-bromo-3-cyano-5-[1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl]-2-thienyl}pyridin-2-yl)carbamate(1.14 g, 2.33 mmol), potassium vinyltrifluoroborate (0.624 g, 4.66mmol), tetrakis(triphenylphosphine)platinum (0) (0.145 g, 0.116 mmol)and potassium carbonate (0.967 g, 7.00 mmol) in N,N-dimethylformamide(14.0 mL) and water (5.0 mL) in a microwave vial was heated undernitrogen atmosphere at 140° C. in a microwave for 15 min. The mixturewas cooled to room temperature, quenched with water, extracted with DCM,washed with water then brine, dried over Na₂SO₄, filtered and rotavapedto give a crude product. Purification on a silica gel column usingMeOH/DCM (0/100 to 5/95) afforded the desired product (1.16 g, with PPh₃and O═PPh₃ contaminated) with Rf on TLC (MeOH/DCM 595) of 0.4, andde-carbamide product (0.627 g, yield 58%). LCMS: (FA) ES+ 437. ¹H NMR(400 MHz, d-chloroform) δ 8.52 (s, 1H), 8.45 (s, 1H), 8.41 (m, 1H), 8.33(s, 1H), 7.51-7.59 (m, 1H), 7.46-7.49 (m, 1H), 6.28-6.33 (m, 1H),5.66-5.69 (m, 1H), 5.51-5.54 (m, 1H), 4.09-4.12 (m, 1H), 3.86 (s, 3H),3.75-3.78 (m, 1H), 2.00-2.20 (m, 3H), 1.68-1.77 (m, 3H).

Step 3: Methyl(4-{3-cyano-4-(1,2-dihydroxyethyl)-5-[1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl]-2-thienyl}pyridin-2-yl)carbamate

To the suspension of methyl(4-{3-cyano-5-[1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl]-4-vinyl-2-thienyl}pyridin-2-yl)carbamate(0.625 g, 1.34 mmol) in tert-butyl alcohol (3.0 mL) and acetone (30 mL)was added N-methylmorpholine N-oxide (0.315 g, 2.69 mmol), followed bywater (1.0 mL) then 0.157 M of osmium tetraoxide in Water (0.257 mL,0.0404 mmol). The pale yellow suspension was stirred at room temperaturefor 17 hours. N-Methylmorpholine N-oxide (0.315 g, 2.69 mmol) was addedand the suspension was stirred for 3 more hours, then heated to refluxfor 7 hours. The mixture was cooled to room temperature, rotavaped andazeotroped with MeOH to give a solid crude residue. The crude solid waspartially dissolved in DCM-MeOH, coated on silica gel, evaporated inrotavapor and chromatographed in a silica gel column using an elution ofMeOH/DCM (0/100 to 5/95) to afford a solid product (0.365 g, yield57.6%). LC/MS: (FA) ES+ 471; ES− 469, ¹H NMR (400 MHz,d-chloroform/d4-methanol) δ 8.35 (m, 2H), 8.30 (m, 1H), 7.40 (m, 1H),5.47-5.49 (m, 1H), 5.31-5.33 (m, 1H), 4.03-4.07 (m, 1H), 3.87 (m, 1H),3.79 (s, 3H), 3.71-3.81 (m, 2H), 2.13 (m, 1H), 2.00-2.02 (m, 2H),1.65-1.70 (m, 3H).

Step 4: Methyl(4-{3-cyano-4-formyl-5-[1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl]-2-thienyl}pyridin-2-yl)carbamate

Methyl(4-{3-cyano-4-(1,2-dihydroxyethyl)-5-[1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl]-2-thienyl}pyridin-2-yl)carbamate(0.362 g, 0.769 mmol) was dissolved in acetone (40 mL) and water (10mL). Sodium metaperiodate (0.494 g, 2.31 mmol) was added and the mixturewas stirred at room temperature for 6 hours. Sodium metaperiodate (0.329g, 1.54 mmol) was added and the mixture was stirred for 16 more hours.The mixture was concentrated in rotavapor. The residue was trituratedwith water, filtered and washed thoroughly with water, then dried inlyophilizer to give a dry solid product (0.320 g, yield 94.8%). LCMS:(FA) ES+ 439. ¹H NMR (400 MHz, d6-dmso) δ 10.67 (s, 1H), 10.57 (s, 1H),9.05 (s, 1H), 8.49 (m, 1H), 8.28 (s, 1H), 7.50 (m, 1H), 5.69-5.73 (m,1H), 3.94-3.98 (m, 1H), 3.73 (s, 3H), 3.66-3.71 (m, 1H), 1.93-2.12 (m,3H), 1.58-1.71 (m, 3H).

Step 5: Methyl(4-{4-[(4-chlorophenyl)(hydroxy)methyl]-3-cyano-5-[1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl]-2-thienyl}pyridin-2-yl)carbamate

To a suspension of methyl(4-{3-cyano-4-formyl-5-[1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl]-2-thienyl}pyridin-2-yl)carbamate(0.1077 g, 0.2456 mmol) in anhydrous Tetrahydrofuran (6.0 mL) cooledwith ice bath was added slowly 1.0 M of 4-chlorophenylmagnesium bromidein ether (2.50 mL, 2.50 mmol). The resulting clear solution was stirredwith cooling for 30 min, then the mixture was quenched with methanol(0.5 mL), then with acetic acid (148 mg, 2.46 mmol). The mixture waswarmed to room temperature, then rotavaped to give crude product, whichwas chromatograph in a silica gel column using MeOH/DCM (0/100 to 3/97)to afford a solid product (0.116 g, yield 82%). LC/MS: (FA) ES+ 551; ES−549, ¹H NMR (400 MHz, d-chloroform/d4-methanol) δ 8.36 (s, 1H), 8.29 (m,2H), 7.43 (m, 1H), 7.34 (m, 2H), 7.19 (m, 2H), 6.37 (s, 1H), 5.41-5.46(m, 1H), 3.99-4.04 (m, 1H), 3.79 (s, 3H), 3.68-3.72 (m, 1H), 2.13 (m,1H), 1.97-2.00 (m, 2H), 1.55-1.70 (m, br, 3H).

Step 6: Methyl{4-[4-[(4-chlorophenyl)(hydroxy)methyl]-3-cyano-5-(4H-1,2,4-triazol-3-yl)-2-thienyl]pyridin-2-yl}carbamate

To a suspension of methyl(4-{4-[(4-chlorophenyl)(hydroxy)methyl]-3-cyano-5-[1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl]-2-thienyl}pyridin-2-yl)carbamate(0.0450 g, 0.0817 mmol) in 1,4-dioxane (4.0 mL, 51 mmol) and cooled inan ice bath was added 6.0 M hydrochloric acid in water (4.0 mL, 24mmol). The resulting solution was brought to room temperature. Hexane(5.0 mL) was added and the bi layer mixture was stirred for 4 hours. Thehexane was separated and the aqueous layer was washed with hexane twice.The aqueous layer was concentrated on a rotavapor to ˜half volume,diluted with ice and water, basified with saturated aqueous NaHCO₃ topH˜7.5, extracted with EtOAc (4×). The combined EtOAc solutions werewashed with brine, dried over Na₂SO₄, filtered, and rotavaped to give acrude solid. The crude solid was chromatographed on a silica gel columnusing MeOH/DCM (0/100 to 5/95) to afford a solid product (33 mg, yield82%). LCMS: (FA) ES+ 467, 469. ¹H NMR (400 MHz, d6-dmso) δ 10.50 (s,1H), 8.82 (s, 1H), 8.41 (m, 1H), 8.20 (s, 1H), 7.57 (m, 2H), 7.39 (m,3H), 7.06 (s, 1H), 6.59 (s, br, 1H), 3.69 (s, 3H).

The compounds in the following table were prepared from the appropriatestarting materials in a method analogous to that of Example 33:

153 LCMS: (AA) ES+ 468. 165 LCMS: (AA) ES+ 451, 453.

Example 34 Synthesis ofN-{4-[4-[(4-chlorophenyl)sulfinyl]-3-cyano-5-(4H-1,2,4-triazol-3-yl)-2-thienyl]pyridin-2-yl}acetamide(Compound 131) andN-{4-[4-[(4-chlorophenyl)sulfonyl]-3-cyano-5-(4H-1,2,4-triazol-3-yl)-2-thienyl]pyridin-2-yl}acetamide(Compound 140)

Step 1:N-(4-{4-bromo-3-cyano-5-[1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl]-2-thienyl}pyridin-2-yl)acetamide

A mixture of2,4-dibromo-5-[1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl]thiophene-3-carbonitrile(1.3809 g, 3.3027 mmol),[B]N-[4-(trimethylstannyl)-pyridin-2-yl]acetamide (987.38 mg, 3.3028mmol), copper(I) iodide (188.70 mg, 0.99082 mmol), lithium chloride(420.04 mg, 9.9082 mmol) and tetrakis(triphenylphosphine)-palladium(0)(190.82 mg, 0.16514 mmol) in dry 1,4-Dioxane (20.0 mL) was sonicatedunder N₂ for 2 min, then heated in a capped vial to 130° C. in microwavemachine for 20 mins. The suspension was cooled to room temperature, andthe residue was purified using silica gel chromatography. The eluent was40-100% ethyl acetate in hexane, affording a solid product (0.8802 g,yield 56.3%) LCMS: (AA) ES+ 473, 475. ¹H NMR (300 MHz, CDCl₃) δ: 8.61(s, 1H), 8.41 (d, 1H), 8.39 (s, 1H), 8.10 (s, 1H), 7.53 (d, 1H),5.55-5.60 (dd, 1H), 4.06-4.10 (m, 1H), 3.68-3.78 (m, 1H), 2.35 (s, 3H),2.15-2.28 (m, 1H), 2.01-2.13 (m, 2H), 1.66-1.80 (m, 3H).

Step 2:N-(4-{4-[(4-chlorophenyl)sulfanyl]-3-cyano-5-[1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl]-2-thienyl}pyridin-2-yl)acetamide

N-(4-{4-bromo-3-cyano-5-[1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl]-2-thienyl}pyridin-2-yl)acetamide(0.2601 g, 0.5495 mmol), copper(I) oxide (0.1572 g, 1.099 mmol),4-chlorobenzenethiol (0.3179 g, 2.198 mmol) and potassium carbonate(0.2278 g, 1.648 mmol) were added to a microwave vial followed by DMF(15.00 mL). The reaction was irradiated at 150° C. for 15 mins. Thesolid was filtered and washed with DCM. The solution was diluted with 80ml water, and extracted with 100 ml DCM for two times. The organic layerwas concentrated, and purified by column. The eluent was 50-100% ethylacetate in hexane to yield a solid product (0.224 g, yield 76.0%) LCMS:(AA) ES+537, 539. ¹H NMR (300 MHz, CDCl₃) δ: 8.59 (s, 1H), 8.37 (d, 1H),8.36 (s, 1H), 8.03 (s, 1H), 7.53 (d, 1H), 7.32 (d, 2H), 7.22 (d, 2H),5.50-5.55 (dd, 1H), 4.02-4.08 (m, 1H), 3.68-3.78 (m, 1H), 2.25 (s, 3H),2.10-2.18 (m, 1H), 2.00-2.07 (m, 2H), 1.66-1.80 (m, 3H).

Step 3:N-(4-(4-(4-chlorophenylsulfinyl)-3-cyano-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl)thiophen-2-yl)pyridin-2-yl)acetamide

N-(4-{4-[(4-chlorophenyl)sulfanyl]-3-cyano-5-[1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl]-2-thienyl}pyridin-2-yl)acetamide(0.0575 g, 0.107 mmol) was dissolved in methylene chloride (5.00 mL),followed by addition of m-chloroperbenzoic acid (0.0194 g, 0.112 mmol).The reaction mixture was stirred at room temperature for 1 hr. Thesolution was concentrated, and purified by column chromatography. Theeluent was 50-100% ethyl acetate in hexane to yield a solid product(0.0324 g, 54.7%) LCMS: (AA) ES+ 553, 555. ¹H NMR (300 MHz, CDCl₃) δ:8.47 (m, 2H), 8.41 (s, 1H), 8.36 (d, 1H), 8.06 (dd, 2H), 7.46 (dd, 2H),7.45 (d, 1H), 5.53-5.59 (dd, 1H), 4.08-4.16 (m, 1H), 3.73-3.81 (m, 1H),2.25 (s, 3H), 2.10-2.18 (m, 1H), 2.00-2.07 (m, 2H), 1.69-1.80 (m, 3H).

Step 4:N-{4-[4-[(4-chlorophenyl)sulfinyl]-3-cyano-5-(4H-1,2,4-triazol-3-yl)-2-thienyl]pyridin-2-yl}acetamide(Compound 131)

N-(4-(4-(4-chlorophenylsulfinyl)-3-cyano-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl)thiophen-2-yl)pyridin-2-yl)acetamide(0.0315 g, 0.0570 mmol) was dissolved in TFA (5.00 mL, 64.9 mmol). Themixture was stirred at room temperature for 1 hr, and the solvent wasevaporated. 10 ml DCM was added to redissolve the material followed bythe addition of triethylamine (1 mL). The solvent was evaporated off,and the mixture was purified by silica gel column. The eluent was 0-6%methanol in hexane to yield a solid product (0.0112 g, yield 41.9%)LCMS: (AA) ES+ 469, 471. 1H NMR (300 MHz, MeOD) δ: 8.65 (s, 1H), 8.51(s, 1H), 8.42 (d, 1H), 8.06 (d, 2H), 7.58 (d, 2H), 7.44 (dd, 1H), 2.25(s, 3H).

Step 5:N-(4-{4-[(4-chlorophenyl)sulfonyl]-3-cyano-5-[1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl]-2-thienyl}-1-oxidopyridin-2-yl)acetamide

N-(4-{4-[(4-chlorophenyl)sulfanyl]-3-cyano-5-[1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl]-2-thienyl}pyridin-2-yl)acetamide(0.0698 g, 0.130 mmol) was dissolved in methylene chloride (6.00 mL)followed by addition of m-Chloroperbenzoic acid (0.08971 g, 0.5199mmol). The mixture was stirred for 30 mins at room temperature. Thesolvent was evaporated, and the residue was purified by columnchromatography. The eluent was 0-7% methanol in ethyl acetate to yield asolid product (0.0654 g, yield 86.0%) LCMS: (AA) ES+ 585, 587. ¹H NMR(300 MHz, CDCl₃) δ: 8.76 (s, 1H), 8.41 (s, 1H), 8.37 (d, 2H), 8.26 (d,1H), 7.50 (d, 2H), 7.43 (d, 1H), 5.50-5.57 (dd, 1H), 4.03-4.10 (m, 1H),3.70-3.78 (m, 1H), 2.25 (s, 3H), 2.10-2.18 (m, 1H), 2.00-2.07 (m, 2H),1.69-1.80 (m, 3H).

Step 6:N-{-4-[4-[(4-chlorophenyl)sulfonyl]-3-cyano-5-(4H-1,2,4-triazol-3-yl)-2-thienyl]-1-oxidopyridin-2-yl}acetamide

N-(4-{4-[(4-chlorophenyl)sulfonyl]-3-cyano-5-[1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl]-2-thienyl}-1-oxidopyridin-2-yl)acetamide(0.0742 g, 0.127 mmol) was dissolved in trifluoroacetic acid (4.00 mL,51.9 mmol). The mixture was stirred at room temperature for 4 hrs,solvent was evaporated and the residue was purified by HPLC to yield asolid product (0.0421 g, yield 66.3%) LCMS: (AA) ES+ 501, 503. 1H NMR(300 MHz, MeOD) δ: 8.90 (s, 1H), 8.60 (s, 1H), 8.43 (d, 1H), 8.35 (d,2H), 7.67 (d, 2H), 7.59 (d, 1H), 2.28 (s, 3H).

Step 7:N-{4-[4-[(4-chlorophenyl)sulfonyl]-3-cyano-5-(4H-1,2,4-triazol-3-yl)-2-thienyl]pyridin-2-yl}acetamide(Compound 140)

N-{4-[4-[(4-chlorophenyl)sulfonyl]-3-cyano-5-(4H-1,2,4-triazol-3-yl)-2-thienyl]-1-oxidopyridin-2-yl}acetamide(0.0229 g, 0.0457 mmol) was dissolved in methanol (3.00 mL), followed bythe addition of 10% Pd—C (5 mg). The flask was filled with hydrogen at40 psi, and the suspension was stirred at room temperature forovernight. The solid was filtered off, and the residue was concentratedfollowed by purification by column chromatography. The eluent was 0-8%methanol in ethyl acetate to yield a solid product (0.0142 g, yield64.0%). LCMS: (AA) ES+ 485, 487. 1H NMR (300 MHz, MeOD) δ: 8.60 (s, 1H),8.53 (s, 1H), 8.45 (d, 1H), 8.35 (d, 2H), 7.66 (d, 2H), 7.48 (d, 1H),2.20 (s, 3H).

The compound in the following table was prepared from the appropriatestarting materials in a method analogous to that of Example 34:

166 LCMS: (AA) ES+ 454

Example 35 Synthesis of5-(4-(4-chlorobenzyl)-2-(pyridin-4-yl)thiazol-5-yl)-1H-pyrazol-3-ol(Compound 178)

Step 1, Preparation of ethyl3-(4-(4-chlorobenzyl)-2-(pyridin-4-yl)thiazol-5-yl)-3-oxopropanoate

To a flask containing 60% NaH in mineral oil (213 mg, 5.32 mmol) undernitrogen was added THF (31.7 mL) and carbonic acid, dimethyl ester(0.448 mL, 5.32 mmol). The mixture was heated to 60 degrees and asolution of 1-(4-(4-chlorobenzyl)-2-(pyridin-4-yl)thiazol-5-yl)ethanone(875 mg, 2.66 mmol) in THF (12.7 mL) was then added. The mixture washeated at 60 degrees for 1 hour. The reaction was cooled and quenchedwith methanol (5 mL), then saturated NH₄Cl (10 mL). The organic solventswere concentrated in vacuo, and the aqueous residue was diluted withwater (10 mL) and extracted with ethyl acetate (2×20 mL). The combinedorganic layers were dried, filtered and concentrated in vacuo. Theresidue was purified by silica gel chromatography (EA/DCM=0/100→40/60)to give 253 mg (25% yield) of the title compound. as an oil. LCMS (FA)ES+ 387, 389. ¹H NMR (300 MHz, CDCl₃) δ: 8.76-8.74 (m, 2H), 7.83-7.81(m, 2H), 7.35-7.32 (m, 2H), 7.26-7.23 (m, 2H), 4.53 (s, 2H), 3.89 (s,2H), 3.77 (s, 3H).

Step 2, Preparation of5-(4-(4-chlorobenzyl)-2-(pyridin-4-yl)thiazol-5-yl)-1H-pyrazol-3-ol

To a solution of ethyl3-(4-(4-chlorobenzyl)-2-(pyridin-4-yl)thiazol-5-yl)-3-oxopropanoate (253mg, 0.631 mmol) in ethanol (16 mL) was added hydrazine hydrate (0.123mL, 2.52 mmol) and the resulting solution was heated to 80 degrees for 3hours. The reaction was cooled and concentrated in vacuo. The residuewas purified by silica gel chromatography (MeOH/DCM=0/100→10/90) to give118 mg of the product. This material was purified by preparative reversephase chromatography to give 63 mg (27% yield) of the title compound. asa white solid. LCMS (FA) ES+ 369, 371. ¹H NMR (300 MHz, DMSO-d₆) δ:12.44 (bs, 1H), 8.68 (bs, 2H), 7.83-7.81 (m, 2H), 7.35-7.32 (m, 2H),7.27-7.24 (m, 2H), 5.60 (s, 1H), 4.34 (s, 2H).

Example 36 Synthesis of(2-(4-(4-chlorobenzyl)-2-(pyridin-4-yl)thiazol-5-yl)-1H-imidazol-4-yl)methanamine(Compound 255)

Step 1, Preparation of 2-(3-bromo-2-oxopropyl)isoindoline-1,3-dione

To a solution of phthalimidoacetone (4.04 g, 19.9 mmol) in methanol (100mL) was added urea (1.19 g, 19.9 mmol) and bromine (3.18 g, 19.9 mmol)and the resulting solution was stirred at room temperature overnight.The reaction was concentrated in vacuo and the residue taken up in DCM(150 mL) and water (50 mL). The layers were separated and the organiclayer was dried, filtered, and concentrated in vacuo. The residue waspurified by silica gel chromatography (EA/hexanes=0/100→50/50) to give159 mg (3% yield) of the title compound. ¹H NMR (300 MHz, CDCl₃) δ:7.90-7.86 (m, 2H), 7.79-7.73 (m, 2H), 4.78 (s, 2H), 4.01 (s, 2H).

Step 2, Preparation of2-((2-(4-(4-chlorobenzyl)-2-(pyridin-4-yl)thiazol-5-yl)-1H-imidazol-4-yl)methyl)isoindoline-1,3-dione

To a mixture of4-(4-chlorobenzyl)-2-(pyridin-4-yl)thiazole-5-carboximidamidehydrochloride (112 mg, 0.306 mmol) in DMF (2.96 mL) was added sodiumcarbonate (162 mg, 1.53 mmol) and2-(3-bromo-2-oxopropyl)isoindoline-1,3-dione (95.0 mg, 0.337 mmol) andthe resulting mixture was heated at 100 degrees for 4 hours. Thereaction was cooled and taken up in ethyl acetate (30 mL) and water (5mL). The layers were separated and the organic layer was washed withwater (3×5 mL). The organic layer was dried, filtered and concentratedin vacuo. The residue was purified by silica gel chromatography(MeOH/DCM=0/100→10/90) to give 47 mg (30% yield) of the title compound.LCMS (FA) ES+ 512. 514. ¹H NMR (300 MHz, DMSO-d₆) δ: 12.67 (bs, 1H),8.69-8.67 (m, 2H), 7.91-7.79 (m, 6H), 7.27-7.24 (m, 3H), 7.11-7.08 (m,2H), 4.77 (s, 2H), 4.45 (s, 2H).

Step 3, Preparation of(2-(4-(4-chlorobenzyl)-2-(pyridin-4-yl)thiazol-5-yl)-1H-imidazol-4-yl)methanamine

To a solution of24(2-(4-(4-chlorobenzyl)-2-(pyridin-4-yl)thiazol-5-yl)-1H-imidazol-4-yl)methyl)isoindoline-1,3-dione(45 mg, 0.0879 mmol) in methanol (2.0 mL) was added hydrazine hydrate(0.0086 mL, 0.176 mmol) and the resulting solution was heated to refluxfor 1 hour. The reaction was cooled and concentrated in vacuo. Theresidue was taken up in ethyl acetate and water. The layers wereseparated and the organic layer was dried, filtered and concentrated invacuo. The residue was purified by silica gel chromatography(MeOH/DCM=0/100→40/60) to give 13 mg (39% yield) of the title compound.LCMS (FA) ES+ 382, 384. ¹H NMR (300 MHz, MeOH-d₄) δ: 8.71-8.68 (m, 2H),7.82-7.80 (m, 2H), 7.35-7.29 (m, 4H), 7.22 (s, 1H), 4.53 (s, 2H), 3.86(s, 2H).

Example 37 Synthesis of5-(4-(4-chlorobenzyl)-2-(pyridin-4-yl)thiazol-5-yl)-1H-pyrazole-3-carboxylicacid (Compound 262)

Step 1, Preparation of ethyl5-(4-(4-chlorobenzyl)-2-(pyridin-4-yl)thiazol-5-yl)-1H-pyrazole-3-carboxylate

An argon degassed mixture of5-bromo-4-(4-chlorobenzyl)-2-(pyridin-4-yl)thiazole (583 mg, 1.59 mmol),ethyl 5-(tributylstannyl)-1H-pyrazole-3-carboxylate (456 mg, 1.06 mmol),tetrakis(triphenylphosphine)palladium(0) (61.4 mg, 0.0531 mmol),copper(I) iodide (60.7 mg, 0.319 mmol), and lithium chloride (135 mg,3.19 mmol) in dioxane (7.46 mL) was heated in a microwave at 150 degreesfor 30 minutes. The reaction mixture was slurried in ethyl acetate (100mL) and water (2 mL) and the mixture was filtered and concentrated invacuo. The residue was purified by silica gel chromatography(EA/DCM=0/100→100/0) to give the crude product. This material waspurified by preparative reverse phase chromatography to give 55 mg (12%yield) of the title compound as a white solid. LCMS (FA) ES+ 425, 427.¹H NMR (300 MHz, DMSO-d₆) δ: 8.71-8.69 (m, 2H), 7.85-7.83 (m, 2H),7.36-7.33 (m, 2H), 7.28-7.25 (m, 2H), 7.09 (s, 1H), 4.41 (s, 2H), 4.34(q, 1H, J=7.2 Hz), 1.31 (t, 1H, J=7.2 Hz).

Step 2, Preparation of5-(4-(4-chlorobenzyl)-2-(pyridin-4-yl)thiazol-5-yl)-1H-pyrazole-3-carboxylicacid

A solution of ethyl5-(4-(4-chlorobenzyl)-2-(pyridin-4-yl)thiazol-5-yl)-1H-pyrazole-3-carboxylate(16.1 mg, 0.0379 mmol) in THF (0.50 mL) was treated with 1.0 M aqueousLiOH (0.0568 mL, 0568 mmol) and the solution was stirred at 40 degreesfor 3 days. The reaction was then heated at 65 degrees for 6 hours. Thereaction mixture was cooled and acidified with 1N HCl. The solution wasextracted with EA (3×25 mL) and the combined organic layers were dried,filtered and concentrated in vacuo. The residue was purified bypreparative reverse phase chromatography to give 1 mg (7% yield) of thetitle compound as a white solid. LCMS (FA) ES+ 397, 399.

Example 38 Synthesis of4-(4-chlorobenzyl)-2-(pyridin-4-yl)-5-(1H-tetrazol-5-yl)thiazole(Compound 190)

Step 1, Preparation of4-(4-chlorobenzyl)-2-(pyridin-4-yl)thiazole-5-carboximidamidehydrochloride and4-(4-chlorobenzyl)-2-(pyridin-4-yl)thiazole-5-carbonitrile

To a suspension of ammonium chloride (2.25 g, 42.1 mmol) in toluene(21.0 mL) in an ice bath was added 2.0 M trimethylaluminum in toluene(21.1 mL, 42.2 mmol) dropwise (gas evolution was observed). The mixturewas then stirred at room temperature for 30 minutes, during which timethe solids dissolved. Ethyl4-(4-chlorobenzyl)-2-morpholinothiazole-5-carboxylate (4.11 g, 11.4mmol) was added in one portion and the resulting solution was heatedslowly to 110° C. over 1 hour, then kept at 110° C. for 2.5 hours. Thereaction was allowed to cool to room temperature overnight. The reactionwas poured into a slurry of silica gel (10 grams) in chloroform (100 mL)and stirred 10 minutes. Methanol (20 mL) was added (bubbling occurred),and the mixture was filtered through a short silica gel bed in asintered glass funnel, eluting with 1:1 methanol/chloroform to removeproduct. The filtrate was concentrated to give the crude product, whichwas purified by silica gel chromatography (MeOH/DCM=0/100→50/0) to give1.6 grams (45% yield) of the nitrile, which eluted first, and 1.9 g (45%yield) of the guanidine, which is the HCl salt. Guanidine: LCMS (FA) ES+329. 331. ¹H NMR (400 MHz, DMSO-d₆) δ: 9.73, (bs, 4H), 8.76-8.74 (m,2H), 7.90-7.88 (m, 2H), 7.39-7.35 (m, 2H), 7.31-7.27 (m, 2H), 4.30 (s,2H). Nitrile: LC/MS (FA) ES+ 312, 314. ¹H NMR (400 MHz, DMSO-d₆) δ:8.77-8.75 (m, 2H), 7.78-7.76 (m, 2H), 7.34-7.29 (m, 4H), 4.29 (s, 2H).

Step 2, Preparation of4-(4-chlorobenzyl)-2-(pyridin-4-yl)-5-(1H-tetrazol-5-yl)thiazole

To a solution 4-(4-chlorobenzyl)-2-(pyridin-4-yl)thiazole-5-carbonitrile(167 mg, 0.536 mmol) in DMF (3.5 mL) was added sodium azide (104 mg,1.61 mmol) and ammonium chloride (86 mg, 1.61 mmol) and the resultingmixture was heated at 100 degrees overnight. The reaction was cooled andtaken up in ethyl acetate and water. The aqueous layer was concentratedin vacuo, and the residue was purified by silica gel chromatography(MeOH/DCM=0/100→10/90) to give 9 mg (5% yield) of the title compound.LC/MS (FA) ES+ 355, 357. ¹H NMR (400 MHz, DMSO-d₆) δ: 8.74-8.73 (m, 2H),7.93-7.92 (m, 2H), 7.38-7.32 (m, 4H), 4.62 (s, 2H).

Example 39 Preparation of3-[hydroxy(2-naphthyl)methyl]-5-pyridin-4-ylthiophene-2-carboxylic acid(Compound 205)

Step 1: Ethyl 5-pyridin-4-ylthiophene-2-carboxylate

A mixture of ethyl 5-bromothiophene-2-carboxylate (1.560 g, 6.65 mmol),pyridine-4-boronic acid (0.98 g, 7.98 mmol),tetrakis(triphenylphosphine)palladium(0) (768 mg, 0.665 mmol) and cesiumcarbonate (6.50 g, 19.9 mmol) in 1,4-dioxane (20 mL) and water (3.35 mL)was stirred and heated at 100° C. under an atmosphere of nitrogenovernight. The reaction was a clear light orange with a small amount ofa second liquid phase on the bottom of the flask. An aliquot was taken,quenched into water, and extracted with ethyl acetate. A TLC on silicagel (1:1 DCM:hexane) indicated that all of the starting material hadbeen consumed. A major new product with Rf˜0.4 was seen. The reactionwas cooled to room temperature then was quenched into stirring water andextracted with ethyl acetate. The ethyl acetate extracts were washedwith saline, dried over sodium sulfate, filtered, and evaporated toleave crude product as an off-white solid. The crude product wasdissolved in minimal DCM then was purified by column chromatography onsilica gel (gradient 100% DCM to 50% ethyl acetate) to afford product1.02 g (66% yield) as white solid. LCMS (FA) ES+ 234. ¹H NMR (400 MHz,DMSO) δ 8.68-8.60 (m, 2H), 7.91-7.83 (m, 2H), 7.78-7.71 (m, 2H),4.37-4.27 (d, J=7.1 Hz, 2H), 1.35-1.27 (t, J=7.1 Hz, 3H).

Step 2: Ethyl3-[hydroxy(2-naphthyl)methyl]-5-pyridin-4-ylthiophene-2-carboxylate

A dry, nitrogen flushed flask, equipped with a stirbar and septum, wascharged with 2,2,6,6-tetramethylpiperidinylmagnesium chloride.lithiumchloride in tetrahydrofuran (1.0M, 1.21 mL, 1.21 mmol). The flask wascooled to −25° C. and a solution of ethyl5-pyridin-4-ylthiophene-2-carboxylate (0.257 g, 1.10 mmol) intetrahydrofuran (1.0 mL, 12 mmol) was added dropwise with stirring. Theresulting dark reddish orange solution was stirred at −25° C. for 30minutes. 2-Naphthalenecarboxaldehyde (0.172 g, 1.10 mmol) was then addeddropwise (as a solution in 1.5 ml THF)— the reaction mixture becamepurple. The reaction was stirred at −25° for 5 minutes, then the coolingbath was removed and the reaction was allowed to warm to roomtemperature with stiffing. An aliquot was removed from the reaction andquenched into sat. NH4Cl solution, then extracted with ethyl acetate. ALCMS of this extract indicated that all starting material had beenconsumed and that the major peak had correct mass for the desiredproduct. The reaction was quenched by the slow dropwise addition of asaturated ammonium chloride solution (5 ml). The resulting yellow-orangemixture was transferred to a separatory funnel and diluted further withwater and ethyl acetate. The organic layer was separated and the aqueouslayer was further extracted with ethyl acetate. The extracts werecombined, washed with saline, dried, and evaporated to leave crudeproduct as an orange oil which was dissolved in minimal dichloromethanethen was purified by column chromatography on silica gel (gradient 100%DCM to 5% MeOH in ethyl acetate) to afford product 210 mg (49% yield) asa white foam. LC/MS (FA) ES+ 390. ¹H NMR (400 MHz, DMSO) δ 8.63-8.58(dd, J=4.6, 1.6 Hz, 2H), 8.04-8.00 (s, 1H), 8.00-7.96 (s, 1H), 7.87-7.81(d, T=8.7 Hz, 3H), 7.76-7.71 (dd, T=4.6, 1.7 Hz, 2H), 7.62-7.58 (d,T=1.6 Hz, 1H), 7.50-7.45 (t, J=3.0 Hz, 2H), 6.74-6.69 (d, J=4.2 Hz, 1H),6.33-6.28 (d, J=4.2 Hz, 1H), 4.37-4.31 (dd, J=7.1, 4.3 Hz, 2H),1.35-1.27 (t, J=7.1 Hz, 3H).

Step 3:3-[Hydroxy(2-naphthyl)methyl]-5-pyridin-4-ylthiophene-2-carboxylic acid(Compound 205)

Ethyl3-[hydroxy(2-naphthyl)methyl]-5-pyridin-4-ylthiophene-2-carboxylate(70.0 mg, 0.180 mmol) was placed in a round bottomed flask equipped witha stirbar. Tetrahydrofuran (2.00 mL), methanol (1.00 mL), and water(1.50 mL) were added with stirring—all solids dissolved. Sodiumhydroxide (1.0 M, 1.50 mL, 1.50 mmol) was added in a single portion andthe resulting solution was stirred under an atmosphere of nitrogenovernight, resulting in a clear light yellow solution. The reaction wasquenched into water and the pH of the mixture was adjusted the pH to˜6-6.5 with sodium bicarbonate solution. The mixture was extracted withethyl acetate, the extracts were combined and then rotovapped to leavecrude product as a light yellow solid. The crude product was purified byHPLC to yield 9 mg (14% yield) product as a pale yellow powder. LC/MS(FA) ES+ 362. ¹H NMR (400 MHz, DMSO) δ 8.60-8.51 (d, J=6.1 Hz, 2H),7.98-7.94 (s, 2H), 7.91-7.75 (m, 4H), 7.68-7.58 (m, 3H), 7.53-7.37 (m,2H), 6.64-6.36 (s, 1H).

Example 40 Preparation of3-(2-naphthylmethyl)-5-pyridin-4-ylthiophene-2-carboxylic acid (Compound210)

Step 1: Ethyl 5-pyridin-4-ylthiophene-2-carboxylate

Ethyl3-[hydroxy(2-naphthyl)methyl]-5-pyridin-4-ylthiophene-2-carboxylate(118.0 mg, 0.3030 mmol), methylene chloride (2.4 mL), trifluoroaceticacid (140.0 uL, 1.818 mmol), and triethylsilane (84.7 uL, 0.530 mmol)were combined in a round bottomed flask equipped with a stirbar. Thereaction was stirred overnight at room temperature under an atmosphereof nitrogen. An aliquot was taken from the reaction, quenched intowater, basified with sodium carbonate, and extracted with ethyl acetate.TLC analysis (2:1 ethyl acetate:DCM) indicated that the starting esterwas ˜50% converted to a slightly higher Rf product. Additionaltrifluoroacetic acid (300 uL, 4 mmol) and triethylsilane (200 uL, 1mmol) were added and the reaction was stirred at room temperature underan atmosphere of nitrogen for another 4 hours. LCMS analysis showed onemajor peak with correct ES+ for product with a small amount of SMremaining. The reaction was quenched into water, basified, and extractedinto ethyl acetate. The extract was washed with saline, dried oversodium sulfate, filtered, and evaporated to leave crude product as anoil. The crude product was dissolved in minimal DCM then was purified bycolumn chromatography on silica gel (gradient 100% DCM to 50% ethylacetate) to afford product 86 mg (76% yield) as a white solid. LCMS (FA)ES+ 374. ¹H NMR (400 MHz, DMSO) δ 8.64-8.55 (m, 2H), 7.90-7.80 (m, 4H),7.80-7.75 (s, 1H), 7.73-7.66 (m, 2H), 7.52-7.40 (m, 3H), 4.57-4.49 (s,2H), 4.39-4.27 (q, J=7.1 Hz, 2H), 1.35-1.25 (t, J=7.1 Hz, 3H).

Step 2: 3-(2-naphthylmethyl)-5-pyridin-4-ylthiophene-2-carboxylic acid(Compound 210)

Ethyl 3-(2-naphthylmethyl)-5-pyridin-4-ylthiophene-2-carboxylate (80.0mg, 0.214 mmol) was placed in a round bottomed flask equipped with astirbar. Methanol (3 mL, 70 mmol) and tetrahydrofuran (3 mL, 40 mmol)were added followed by water (2 mL, 100 mmol). The resulting solutionwas stirred and lithium hydroxide in water (1.0 M, 0.643 mL, 0.643 mmol)was added. The flask was sealed and stirred overnight at RT. LCMS of analiquot indicated that all starting material had been consumed to give asingle product with the correct mass for the desired product. To thestirring reaction was added ˜30 mL water and a few mL saline. Themixture was stirred and acidified to ˜pH 1 with 1N HCl—a gelatinousprecipitate formed. The mixture was stirred rapidly and diethyl ether(10 mL) was added—the precipitate became more granular and becamesuspended mostly in the organic layer. The quench mixture was stirred atroom temperature for ˜30 minutes then the solid was collected on afritted funnel, washed well with water then diethyl ether, then dried invacuo to yield product 60 mg (81% yield) as a white powder. LC/MS (FA)ES+ 346. ¹H NMR (400 MHz, DMSO) δ 13.62-13.20 (s, 1H), 8.63-8.52 (dd,J=4.7, 1.5 Hz, 2H), 7.91-7.80 (m, 3H), 7.80-7.72 (d, J=3.0 Hz, 2H),7.70-7.63 (dd, J=4.6, 1.5 Hz, 2H), 7.53-7.40 (m, 3H), 4.57-4.48 (s, 2H).

Example 41 Synthesis of2-(2-acetamidopyridin-4-yl)-4-(naphthalen-2-ylmethyl)thiazole-5-carboxylicacid (Compound 177)

Step 1, Preparation of ethyl2-(2-acetamidopyridin-4-yl)-4-bromothiazole-5-carboxylate

A mixture of ethyl 2,4-dibromothiazole-5-carboxylate (0.500 g, 1.59mmol), N-(4-(trimethylstannyl)pyridin-2-yl)acetamide (0.569 g, 1.90mmol), tetrakis(triphenylphosphine)palladium(0) (91.7 mg, 0.0794 mmol),copper(I) iodide (90.7 mg, 0.476 mmol), and lithium chloride (202 mg,4.76 mmol) in dioxane (29.1 mL) was degassed with nitrogen and heated atreflux for 1 hr. The reaction was cooled and concentrated in vacuo. Theresidue was purified by silica gel chromatography (ethylacetate/hexane=0/100→50/50) to give 312 mg of the title compound. (44%yield). LCMS (FA) ES+370, 372. ¹H NMR (400 MHz, CDCl₃) δ: 8.71 (s, 1H),8.39 (d, 1H, J=5.2 Hz), 8.25 (bs, 1H), 7.68 (dd, 1H, J=5.2, 1.6 Hz),4.41 (q, 2H, J=7.2 Hz), 2.26 (s, 3H), 1.41 (t, 3H, J=7.2 Hz).

Step 2, Preparation of ethyl2-(2-acetamidopyridin-4-yl)-4-(naphthalen-2-ylmethyl)thiazole-5-carboxylate

To a mixture of ethyl2-(2-acetamidopyridin-4-yl)-4-bromothiazole-5-carboxylate (190 mg, 0.510mmol) and bis(tri-t-butylphosphine)palladium(0) (65.6 mg, 0.128 mmol)under nitrogen was added a 0.500 M solution of 2-napthylmethylzincbromide in THF (3.60 mL, 1.80 mmol). The reaction was stirred at roomtemperature for 5 minutes, then at 60 degrees for 1 hour. Anotherportion of bis(tri-t-butylphosphine)palladium(0) (60.0 mg, 0.117 mmol)was added, followed by another portion of 0.500 M solution of2-napthylmethylzinc bromide in THF (3.00 mL, 1.50 mmol), and thereaction was heated at 60 degrees for an additional 45 minutes. Thereaction was cooled to room temperature and quenched with saturatedammonium chloride (10 mL). The mixture was extracted with ethyl acetate(2×20 mL) and the combined organic layers were dried over MgSO₄,filtered, and concentrated in vacuo. The residue was purified by silicagel chromatography (ethyl acetate/hexane=0/100→100/0) to give 100 mg ofthe title compound. (40% yield). LCMS (FA) ES+ 432.

Step 3, Preparation of2-(2-aminopyridin-4-yl)-4-(naphthalen-2-ylmethyl)thiazole-5-carboxylicacid, HCl salt

To a mixture of ethyl2-(2-acetamidopyridin-4-yl)-4-(naphthalen-2-ylmethyl)thiazole-5-carboxylate(100 mg, 0.232 mmol) in THF (2.00 mL) was added 1.0 M aqueous LiOH (2.32mL, 2.32 mmol) and the resulting mixture was heated at 40 degrees for 3days. The mixture was acidified with 1N HCl and the resultingprecipitate was filtered and dried to give the 85 mg of the crude HClsalt (100% yield) which was used as is in the next step. LCMS (FA) ES+362.\

Step 4, Preparation of2-(2-acetamidopyridin-4-yl)-4-(naphthalen-2-ylmethyl)thiazole-5-carboxylicacid

a solution of(2-aminopyridin-4-yl)-4-(naphthalen-2-ylmethyl)thiazole-5-carboxylicacid, HCl salt (85.0 mg, 0.214 mmol) in acetic anhydride (1.15 mL, 12.2mmol) and pyridine (0.300 mL, 3.71 mmol) was added DMAP (0.30 mg, 0.0024mmol) and the resulting solution was stirred at room temperatureovernight. The reaction was concentrated in vacuo and the residue waspurified by silica gel chromatography (MeOH/DCM=0/100→40/60) to give 20mg of the title compound (23% yield). LC/MS (FA) ES+ 404. ¹H NMR (400MHz, DMSO-d₆) δ: 13.84 (bs, 1H), 10.71 (s, 1H), 8.63 (s, 1H), 8.41 (d,1H, J=5.2 Hz), 7.86-7.82 (m, 3H), 7.76 (s, 1H), 7.57 (dd, 1H, J=5.2, 1.2Hz), 7.49-7.42 (m, 3H), 4.70 (s, 2H), 2.10 (s, 3H).

The following analytical methods were used for examples below:

LCMS sectra were run on a Phenominex Luna 5 μm C18 50×4.6 mm column on aHewlett-Packard HP1100 using the following gradients:

Method Formic Acid (FA): Acetonitrile containing 0 to 100 percent 0.1%formic acid in water (2.5 ml/min for a 3 minute run).

Method Ammonium Acetate (AA): Acetonitrile containing 0 to 100 percent10 mM ammonium acetate in water (2.5 ml/min for a 3 minute run).

Chiral isomers were separated using chiral HPLC on a Chiralpak IC 250×25mm 5 micron column using hexane/ethanol/diethylamine orhexane/isopropyl/alcohol/ethanol/diethylamine as mobil phase. Absoluteconfigurations of the separated isomers were unknown, structures wereassigned arbitrarily.

NMR spectrum is shown by proton NMR, with tetramethylsilane as theinternal standard and using 300 MHz Bruker Avance spectrometer equippedwith a 5 mm QNP probe and 400 MHz Bruker Avance II spectrometer equippedwith a 5 mm QNP probe for the measurement; δ values are expressed inppm.

Example 42 Synthesis of3-(4-chloro-3-fluorobenzyl)-4-cyano-5-morpholin-4-ylthiophene-2-carboxylicacid (Compound 94)

Step 1: Ethyl 4-cyano-3-iodo-5-morpholin-4-ylthiophene-2-carboxylate

To a 500 mL RBF containing ethyl4-cyano-3-iodo-5-(methylsulfonyl)thiophene-2-carboxylate (17.20 g, 44.65mmol, prepared as in WO 2009154741) was added anhydrous 1,4-dioxane(172.0 mL, 2204 mmol). To the resulting suspension was added morpholine(8.177 mL, 93.77 mmol). A reflux condenser was attached and thepink/orange heterogeneous suspension was heated to bath temp 90° C. andallowed to stir. Shortly after heating began, reaction mixture became acherry red, homogenous solution. Reaction was stirred for 16 hours at90° C. The reaction was then cooled to room temperature and diluted withwater (100 mL). Mixture was filtered, and the solid was dried for invacuo at 40° C. for 5 days to afford ethyl4-cyano-3-iodo-5-morpholin-4-ylthiophene-2-carboxylate (14.3 grams, 82%yield). LCMS: (FA) ES+ 393; ¹H NMR (400 MHz, DMSO) δ 4.24 (q, J=7.1,2H), 3.78-3.70 (m, 4H), 3.63-3.57 (m, 4H), 1.26 (t, J=7.1, 3H).

Step 2: Ethyl3-(4-chloro-3-fluorobenzyl)-4-cyano-5-morpholin-4-ylthiophene-2-carboxylate

In a flame-dried scintillation vial, to a suspension of zinc (0.0998 g,1.53 mmol) in N,N-dimethylformamide (1.36 mL, 17.6 mmol) were added1,2-dibromoethane (0.003279 mL, 0.03805 mmol) and chlorotrimethylsilane(0.004830 mL, 0.03805 mmol). Stirred at room temperature for 15 min, atwhich point a solution of 3-fluoro-4-chlorobenzylbromide (0.341 g, 1.53mmol) in N,N-dimethylformamide (1.36 mL, 17.6 mmol) was added. Theresulting suspension was stirred at room temperature for 16 hours. Ascintillation vial containing ethyl4-cyano-3-iodo-5-morpholin-4-ylthiophene-2-carboxylate (199 mg, 0.507mmol and bis(tri-t-butylphosphine)palladium(0) (12.96 mg, 0.02537 mmol)was purged via vacuum/backfilling with argon. To this was added theorganozinc solution from above, and the resulting solution was stirredat 45° C. for 6 hours, at which point LCMS showed complete conversion toa single new peak with mass representing desired product. The reactionmixture was transferred to a separatory funnel containing saturatedNaHCO₃ (aq., 10 mL) and water (10 mL), and then diluted with EtOAc (40mL). The layers were separated, and the aqueous layer was extracted 2×30mL with EtOAc. The combined organic layers were washed 1× brine, driedover Na₂SO₄, filtered, and concentrated in vacuo to afford crude ethyl3-(4-chloro-3-fluorobenzyl)-4-cyano-5-morpholin-4-ylthiophene-2-carboxylateas a brown oil that was used without further purification. LCMS: (FA)ES+ 409, 411

Step 3:3-(4-Chloro-3-fluorobenzyl)-4-cyano-5-morpholin-4-ylthiophene-2-carboxylicacid (Compound 94)

To a solution of ethyl3-(4-chloro-3-fluorobenzyl)-4-cyano-5-morpholin-4-ylthiophene-2-carboxylatein tetrahydrofuran (5.64 mL, 69.6 mmol) was added methanol (2.5 mL, 62mmol) and 1 M sodium hydroxide in water (4.23 mL, 4.23 mmol) and theresulting suspension was stirred at room temp. The reaction was stirredfor 16 hours at room temperature. Volatiles were then removed in vacuo,and the residue diluted with EtOAc (30 mL). Mixture was then transferredto a separatory funnel containing 1N HCl (5.0 mL) and water (10 mL), atwhich time the pH of aqueous layer was measured at 2.0. Layers wereseparated, and the aqueous layer was extracted 3×20 mL with EtOAc.Combined organic layers were dried over Na₂SO₄, filtered, concentratedin vacuo. Resulting residue was adsorbed to celite, and the resultingsolid was placed into a dryload cartridge and purified via columnchromatography (gradient elution, 0-5% MeOH:CH₂Cl₂) to afford3-(4-chloro-3-fluorobenzyl)-4-cyano-5-morpholin-4-ylthiophene-2-carboxylicacid (94) as a white solid (0.128 g, yield 66.3%). LCMS: (FA) ES+ 381,383; ¹H NMR (400 MHz, DMSO) δ 13.25 (s, 1H), 7.52 (dd, J=8.1, 8.1, 1H),7.22 (dd, J=1.9, 10.5, 1H), 7.05 (dd, J=1.5, 8.3, 1H), 4.31 (s, 2H),3.80-3.65 (dd, J=4.5, 5.2, 4H), 3.59-3.47 (dd, J=4.5, 5.2, 4H).

Compounds in the following table are prepared from appropriate startingmaterials in a method analogous to that of Example 42.

96 LC/MS: (FA) ES− 395, 397 97 LC/MS: (AA) ES+ 347 102 LC/MS: (FA) ES−411 105 LC/MS: (AA) ES+ 359 106 LC/MS: (FA) ES− 405, 407 107 LC/MS: (FA)ES− 381 108 LC/MS: (FA) ES+ 393, 395 112 LC/MS: (FA) ES+ 379 115 LC/MS:(FA) ES+ 354 116 LC/MS: (FA) ES+ 363 117 LC/MS: (FA) ES− 391, 393 122LC/MS: (FA) ES− 391, 393 123 LC/MS: (FA) ES+ 381 124 LC/MS: (FA) ES−395, 397 125 LC/MS: (FA) ES+ 393, 395 126 LC/MS: (FA) ES− 397, 399 127LC/MS: (FA) ES− 409, 411 300 LC/MS: (FA) ES− 397

Example 43 Synthesis of3-(4-chlorobenzyl)-4-cyano-5-(3,6-dihydro-2H-pyran-4-yl)thiophene-2-carboxylicacid (Compound 95)

Step 1:Ethyl-3-bromo-4-cyano-5-(3,6-dihydro-2H-pyran-4-yl)thiophene-2-carboxylate

To a microwave vial containing a suspension of ethyl3,5-dibromo-4-cyanothiophene-2-carboxylate (300.0 mg, 0.8849 mmol,prepared as in MPI10-008P1M) and 3,6-dihydro-2 h-pyran-4-boronic acidpinacol ester (204 mg, 0.973 mmol) in 1,4-dioxane (8.98 mL, 115 mmol)and water (0.925 mL, 51.3 mmol) were addedtetrakis(triphenylphosphine)palladium(0) (102 mg, 0.0885 mmol) andcesium carbonate (865 mg, 2.65 mmol). The vial was sealed, degassed bybubbling argon through for 10 minutes, and then heated at 100° C. withstirring for 24 h. The reaction was then cooled to room temperature andpartitioned between EtOAc and water. Layers were separated, and theaqueous layer was extracted 2× with EtOAc. Combined organic layers weredried over Na₂SO₄, filtered, and concentrated in vacuo. Residue wassubjected to column chromatography as a solution in DCM (40 g column,gradient elution 0 to 25% EtOAc/hexanes) to afford ethyl3-bromo-4-cyano-5-(3,6-dihydro-2H-pyran-4-yl)thiophene-2-carboxylate asa white solid (183 mg, yield 63%). LCMS: (FA) ES+ 342, 344; ¹H NMR (400MHz, DMSO) δ 6.86-6.79 (m, 1H), 4.36-4.27 (m, 4H), 3.82 (dd, J=5.4, 5.4,2H), 2.53 (ddd, J=2.1, 4.9, 10.0, 2H), 1.30 (dd, J=7.1, 7.1, 3H).

Step 2: Ethyl3-(4-chlorobenzyl)-4-cyano-5-(3,6-dihydro-2H-pyran-4-yl)thiophene-2-carboxylate

In a sealable reaction vial, ethyl3-bromo-4-cyano-5-(3,6-dihydro-2H-pyran-4-yl)thiophene-2-carboxylate(180.0 mg, 0.5260 mmol) and a stir pea were azeotroped with toluene 3×and dried under high vacuum overnight. To the vial was addedbis(tri-t-butylphosphine)palladium(0) (26.88 mg, 0.05260 mmol). Vial wasevacuated and then back-filled with argon 2×, at which time was addedvia syringe 4-chlorobenzylzinc chloride as a 0.50 M solution intetrahydrofuran (3.682 mL, 1.841 mmol). The reaction was heated withstiffing at 60° C. for 2 h. Reaction was cooled to room temperature andthen diluted with EtOAc and sat. aq. NH₄Cl. Mixture was transferred to aseparatory funnel, the layers were separated, and the aqueous layerextracted 2× with EtOAc. The combined organic layers were washed withbrine, dried over Na₂SO₄, filtered through a pad of Celite, andconcentrated in vacuo to afford a yellow oil. The residue was dissolvedin DCM and loaded onto 40 g ISCO column (gradient elution: 0-25%EtOAc/hexanes) to afford ethyl3-(4-chlorobenzyl)-4-cyano-5-(3,6-dihydro-2H-pyran-4-yl)thiophene-2-carboxylate(92 mg, 43.6%) as a yellow solid. LC/MS: (AA) ES-386, 388; ¹H NMR (400MHz, DMSO) δ 7.38-7.33 (m, 2H), 7.22 (m, 2H), 6.80-6.76 (m, 1H), 4.40(s, 2H), 4.34-4.24 (m, 4H), 3.80 (dd, J=5.4, 5.4, 2H), 2.52 (dd, J=2.2,5.0, 2H), 1.26 (dd, J=7.1, 7.1, 3H).

Step 3:3-(4-chlorobenzyl)-4-cyano-5-(3,6-dihydro-2H-pyran-4-yl)thiophene-2-carboxylicacid (Compound 95)

To a round bottom flask containing ethyl3-(4-chlorobenzyl)-4-cyano-5-(3,6-dihydro-2H-pyran-4-yl)thiophene-2-carboxylate(43.0 mg, 0.111 mmol) were added tetrahydrofuran (1.23 mL, 15.2 mmol),sodium hydroxide (1.0N in water, 0.925 mL, 0.925 mmol), and methanol(0.617 mL, 15.2 mmol). The mixture was stirred at room temperatureovernight. Reaction was quenched via addition of 1N HCl in water (2 mL),then diluted with EtOAc and transferred to separatory funnel. The layerswere separated, and the aqueous layer was extracted 2× with EtOAc.Combined organics were washed with brine, dried over Na₂SO₄, andfiltered, at adsorbed to Celite (10 mL). Column chromatography (40 gISCO column, gradient elution 0-8% MeOH/DCM afforded3-(4-chlorobenzyl)-4-cyano-5-(3,6-dihydro-2H-pyran-4-yl)thiophene-2-carboxylicacid (95) (25 mg, 63%) as a white solid. LC/MS: (FA) ES− 358, 360; ¹HNMR (400 MHz, DMSO) δ 14.04 (br s, 1H), 7.33 (d, J=8.5, 2H), 7.26 (d,J=8.5, 2H), 6.64 (s, 1H), 4.43 (s, 2H), 4.24 (d, J=2.9, 2H), 3.79 (dd,J=5.4, 5.4, 2H), 3.32 (br s, 2H).

Example 44 Synthesis of4-(4-chloro-3-fluorobenzyl)-2-morpholin-4-yl-1,3-thiazole-5-carboxylicacid (Compound 118)

Step 1: Ethyl 2,4-dibromo-1,3-thiazole-5-carboxylate

In a 50 mL 2-neck RBF equipped with septa, a solution ofN,N-Diisopropylamine (0.04374 g, 0.4322 mmol) in tetrahydrofuran (1.33mL, 16.4 mmol) under atmosphere of argon was cooled at −78° C., at whichpoint n-butyllithium (2.50 M in hexane, 0.1647 mL, 0.4116 mmol) wasadded dropwise and the resulting solution was stirred for 30 minutes at−78° C. To the above solution was added dropwise a solution of2,4-dibromothiazole (0.100 g, 0.412 mmol) in tetrahydrofuran (1.33 mL,16.4 mmol) at −78° C., and this solution was stirred for 30 min −78° C.Next, ethyl chloroformate (0.07872 mL, 0.8233 mmol) was added dropwiseat −78° C. and the mixture was stirred for 30 minutes. The reaction wasquenched by addition of water (20 mL), the layers were separated, andthe aqueous layer was extracted with ethyl acetate (3×20 mL). Thecombined organic layers were washed with brine, dried over Na₂SO₄,filtered, and concentrated in vacuo. The residue was purified via silicagel column chromatography (12 g Analogix column, gradient elution 5% to10% EtOAc in hexane) to afford ethyl2,4-dibromo-1,3-thiazole-5-carboxylate (60 mg, yield 46%). LC/MS: (FA)ES+ 314, 316, 318; ¹H NMR (400 MHz, CDCl₃) δ 4.37 (q, J=7.1, 2H),1.44-1.33 (m, 3H).

Step 2: Ethyl 4-bromo-2-morpholin-4-yl-1,3-thiazole-5-carboxylate

In a sealable reaction vessel, to a suspension of ethyl2,4-dibromo-1,3-thiazole-5-carboxylate (2.90 g, 9.21 mmol, prepared asin WO 2005026149) and cesium carbonate (9.00 g, 27.6 mmol) intetrahydrofuran (24.3 mL, 299 mmol) was added morpholine (0.883 mL, 10.1mmol), at which point the vessel was sealed and the mixture was heatedwith stirring at 90° C. for 4 hours. Reaction mixture was diluted withEtOAc and water and transferred to a separatory funnel. Layers wereseparated, and the organic layer was washed with water, dried overNa₂SO₄, filtered, and concentrated in vacuo. Residue was subjected tocolumn chromatography (gradient elution, 0 to 50% EA in hexanes) toafford ethyl 4-bromo-2-morpholin-4-yl-1,3-thiazole-5-carboxylate (2.4 g,yield 81%) as a white solid. LC/MS: (FA) ES+ 321, 323; ¹H NMR (300 MHz,CDCl₃) δ 4.30 (dd, J=7.1, 7.1, 2H), 3.82-3.75 (m, 4H), 3.58-3.50 (m,4H), 1.34 (dd, J=7.1, 7.1, 3H).

Step 3:Ethyl-4-(4-chloro-3-fluorobenzyl)-2-morpholin-4-yl-1,3-thiazole-5-carboxylate

In a 50 ml flame-dried round bottom flask, a suspension of zinc (0.183g, 0.00280 mol), chlorotrimethylsilane (8.9 uL, 0.000070 mol) and1,2-dibromoethane (6.0 uL, 0.000070 mol) in N,N-dimethylformamide (2.4mL, 0.031 mol) was stirred for 15 minutes. To this was added a solutionof 3-fluoro-4-chlorobenzylbromide (0.626 g, 0.00280 mol) inN,N-dimethylformamide (4.8 mL, 0.062 mol), and the resulting suspensionwas stirred overnight at room temperature. To a flame-dried 50 ml roundbottom flask containing ethyl4-bromo-2-morpholin-4-yl-1,3-thiazole-5-carboxylate (0.300 g, 0.000934mol) and bis(tri-t-butylphosphine)palladium(0) (36 mg, 0.000070 mol) wasadded the organozinc solution from above, and the reaction was heatedwith stirring at 60° C. for 60 min. Reaction was quenched with saturatedammonium chloride, and then transferred to a separatory funnelcontaining water (10 mL) and EtOAc (40 mL). The layers were separated,and the aqueous layer was extracted 2×30 mL with EtOAc. The combinedorganic layers were washed 1× brine, dried over Na₂SO₄, filtered, andconcentrated in vacuo. The resulting residue was dissolved in DCM,adsorbed onto silica gel and purified via column chromotography (24 gramIsco column, gradient elution, 0-50% EtOAc hexanes) to afford ethyl4-(4-chloro-3-fluorobenzyl)-2-morpholin-4-yl-1,3-thiazole-5-carboxylate(245 mg, yield 68.2%).

Step 4:4-(4-chloro-3-fluorobenzyl)-2-morpholin-4-yl-1,3-thiazole-5-carboxylicacid (Compound 118)

In a 50 mL round bottom flask were combined ethyl4-(4-chloro-3-fluorobenzyl)-2-morpholin-4-yl-1,3-thiazole-5-carboxylate(0.245 g, 0.000637 mol), tetrahydrofuran (5.49 mL, 0.0677 mol) and asolution of lithium hydroxide (2.0 M in water, 3.18 mL, 0.00637 mol).The mixture was heated at 80° C. with stirring for 2 days, and thencooled to room temperature and diluted with water. Reaction mixture wasthen carefully adjusted to pH 5 via addition of 1N HCl and transferredto a separatory funnel containing EtOAc (40 mL). Layers were separated,and the aqueous layer was extracted 2×30 mL with EtOAc. The combinedorganic layers were washed 1× brine, dried over Na₂SO₄, filtered, andconcentrated in vacuo to afford a white solid, which was dissolved inDCM and adsorbed onto silica gel. Column chromatography (4 g column,gradient elution 0-20% MeOH in DCM) then afforded4-(4-chloro-3-fluorobenzyl)-2-morpholin-4-yl-1,3-thiazole-5-carboxylicacid (118) (31 mg, 14%). LC/MS: (FA) ES+ 357, 359; ¹H NMR (400 MHz,DMSO) δ 12.79 (s, 1H), 7.48 (t, J=8.1, 1H), 7.24 (dd, J=1.9, 10.5, 1H),7.08 (dd, J=1.5, 8.3, 1H), 4.24 (s, 2H), 3.71-3.62 (m, 4H), 3.46-3.38(m, 4H).

Compounds in the following table are prepared from appropriate startingmaterials in a method analogous to that of Example 44

91 LC/MS: (FA) ES+ 339 93 LC/MS: (FA) ES+ 330 98 LC/MS: (FA) ES+ 355 101LC/MS: (FA) ES+ 357, 359 103 LC/MS: (FA) ES+ 335 104 LC/MS: (FA) ES+373, 375, 377 109 LC/MS: (FA) ES+ 389 111 LC/MS: (FA) ES+ 373 114 LC/MS:(FA) ES+ 373, 375, 377 119 LC/MS: (FA) ES+ 323 120 LC/MS: (FA) ES+ 369,371

Example 45 Synthesis of4-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)-2-(morpholin-4-yl)-1,3-thiazole-5-carboxylicacid (Compound 110)

Step 1: Butanoic acid, 2-chloro-3-oxo-, ethyl ester

In a 500 mL round bottomed flask, to a solution of 3-oxobutanoic acidethyl ester (7.69 mL, 60.3 mmol) in methylene chloride (150 mL, 2300mmol) at 0° C. was slowly added sulfuryl chloride (6.30 mL, 77.8 mmol).The mixture was stirred for 3 hours, and then quenched with saturatedNaHCO₃. Mixture was transferred to a separatory funnel the layers wereseparated. The organic layer was washed 1× brine, dried with Na₂SO₄,filtered, and concentrated in vacuo to afford butanoic acid,2-chloro-3-oxo-, ethyl ester which was immediately used without furtherpurification.

Step 2: Ethyl 4-methyl-2-(morpholin-4-yl)-1,3-thiazole-5-carboxylate

In a 100 mL round bottomed flask, to a solution of butanoic acid,2-chloro-3-oxo-, ethyl ester (11.2 g, 68.4 mmol) in isopropyl alcohol(250 mL, 3300 mmol) was added morpholine-4-carbothioicacidamide (10.0 g,68.4 mmol). The mixture was stirred at reflux for 1 hour, and thenstirred at room temperature for 3 days. Volatiles were removed in vacuo,and the resulting residue was dissolved in ethyl acetate and dilutedwith saturated, aqueous sodium bicarbonate. The mixture was transferredto a separatory funnel, the layers were separated, and the organic layerdried with Na2SO4, filtered and concentrated in vacuo. The crude productwas dissolved in DCM, adsorbed onto silica gel, and purified via columnchromatography (120 g Isco column, gradient elution, 0-100%EtOAc/hexanes) to afford ethyl4-methyl-2-(morpholin-4-yl)-1,3-thiazole-5-carboxylate (14.51 g, yieldfor 2 steps, 82%). LC/MS: (FA) ES+ 257, 259; ¹H NMR (400 MHz, CDCl₃) δ4.26 (dd, J=7.1, 7.1, 2H), 3.87-3.67 (m, 4H), 3.59-3.42 (m, 4H), 2.55(s, 3H), 1.33 (dd, J=7.1, 7.1, 3H).

Step 3: Ethyl4-(bromomethyl)-2-(morpholin-4-yl)-1,3-thiazole-5-carboxylate

To a round bottom flask containing a solution ofethyl-4-methyl-2-(morpholin-4-yl)-1,3-thiazole-5-carboxylate (14.50 g,56.57 mmol) in methylene chloride (400 mL, 6000 mmol) were addedN-bromosuccinimide (10.07 g, 56.57 mmol) and2,2′-azo-bis-isobutyronitrile (464 mg, 2.83 mmol). The mixture wasstirred at reflux overnight. Reaction was quenched via addition of 10%aqueous sodium bisulfite (20 g in 200 ml water) and stirred for 20minutes. Mixture was transferred to a separatory funnel, the layersseparated, and the aqueous layer was extracted 2×DCM. Combined organiclayers were dried with Na₂SO₄, filtered, and concentrated in vacuo. Theresulting residue was dissolved in DCM and adsorbed onto silica gel.Purification via column chromatography (220 g Isco column, gradientelution 0-10% EtOAc in 1:1 DCM:hexanes) afforded ethyl4-(bromomethyl)-2-(morpholin-4-yl)-1,3-thiazole-5-carboxylate (13.5 g,yield 71.1%). LC/MS: (FA) ES+ 335, 337; ¹H NMR (300 MHz, CDCl₃) δ 4.76(s, 2H), 4.30 (dd, J=7.1, 7.1, 2H), 3.88-3.72 (m, 4H), 3.62-3.49 (m,4H), 1.35 (dd, J=7.1, 7.1, 3H).

Step 4: Ethyl4-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)-2-(morpholin-4-yl)-1,3-thiazole-5-carboxylate

Ethyl 4-(bromomethyl)-2-(morpholin-4-yl)-1,3-thiazole-5-carboxylate(109.4 mg, 0.326 mmol), 1,4-benzodioxane-6-boronic acid (91.0 mg, 0.506mmol), tetrakis(triphenylphosphine)palladium(0) (43.0 mg, 0.0372 mmol),cesium carbonate (430 mg, 1.3 mmol), 1,4-dioxane (2.19 mL, 28.0 mmol)and water (43.8 uL, 2.43 mmol) were combined in a vial equipped with astirbar. The vial was sealed and the atmosphere was replaced withnitrogen. The vial was sonicated for 1 minute then heated at 90° C.(heating block temperature) with stirring for 1 hour. The reaction wascooled to room temperature, the vial was opened and the contents werequenched into stirring saline. The quench mixture was transferred to aseparatory funnel and extracted twice with ethyl acetate. The extractswere combined, washed with saline, dried over sodium sulfate, filtered,and concentrated in vacuo to leave an orange oil. The crude residue waspurified by silica gel chromatography (gradient elution: ethylacetatehexane from 0/100 to 100/0) to give ethyl4-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)-2-(morpholin-4-yl)-1,3-thiazole-5-carboxylate(60 mg, 47% yield) as a white powder. LCMS (FA) ES+ 391; ¹H NMR (300MHz, DMSO-d6) δ: 6.67-6.74 (m, 3H), 4.20 (q, 2H, J=7.1 Hz), 4.17 (s,4H), 4.07 (s, 2H), 3.69-3.65 (m, 4H), 3.46-3.43 (m, 4H), 1.24 (t, 3H,J=7.1 Hz).

Step 5:4-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)-2-(morpholin-4-yl)-1,3-thiazole-5-carboxylicacid (Compound 110)

Ethyl4-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)-2-(morpholin-4-yl)-1,3-thiazole-5-carboxylate(58.0 mg, 0.000148 mol) was placed in a 50 ml round bottom flaskequipped with a stirbar. Tetrahydrofuran (2.25 mL, 0.0277 mol) andmethanol (0.50 mL, 0.012 mol) were added and the mixture was stirred togive a clear solution. A solution of lithium hydroxide in water (2.0M,0.750 mL, 0.00150 mol) was added in a single portion, resulting in apale yellow solution which was stirred at room temperature under anatmosphere of nitrogen for 15 minutes. The reaction was then heated atreflux for 2.5 hours, cooled to rt, and diluted with water (˜25 ml) togive a clear slightly gray solution, which was allowed to stir at roomtemperature overnight under an atmosphere of nitrogen. 1 N HCl (˜1.8 ml)was slowly added to the stiffing solution to lower the pH to ˜3 (pHpaper) whereupon a white precipitate formed. The mixture was stirred for˜15 minutes, at which point the solid was collected on a fritted funnel,washed with water, and dried on the funnel with house vacuum under astream of nitrogen for several hours to yield4-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)-2-(morpholin-4-yl)-1,3-thiazole-5-carboxylicacid (110) (45 mg, 84% yield) as a slightly gray powder. LC/MS (FA) ES+363; ¹H NMR (300 MHz, DMSO) δ 12.65 (s, 1H), 6.76-6.64 (m, 3H), 4.17 (s,4H), 4.08 (s, 2H), 3.77-3.61 (m, 4H), 3.51-3.34 (m, 4H).

Compounds in the following table are prepared from appropriate startingmaterials in a method analogous to that of Example 45.

99 LC/MS: (FA) ES+ 357, 359 128 LC/MS: (AA) ES+ 373 286 LC/MS: (FA) ES+361 288 LC/MS: (AA) ES+ 385 289 LC/MS: (FA) ES+ 376 290 LC/MS: (FA) ES+391, 393, 395 292 LC/MS: (AA) ES+ 356 299 LC/MS: (AA) ES+ 373 302 LC/MS:(FA) ES+ 358 303 LC/MS: (FA) ES+ 439, 441 310 LC/MS: (AA) ES+ 373 314LC/MS: (AA) ES+ 373 318 LC/MS: (FA) ES+ 398 319 LC/MS: (AA) ES+ 373 325LC/MS: (FA) ES+ 380 328 LC/MS: (FA) ES+ 344 335 LC/MS: (AA) ES+ 385 338LC/MS: (AA) ES+ 373 339 LC/MS: (FA) ES+ 365 340 LC/MS: (AA) ES+ 373 341LC/MS: (AA) ES+ 345 344 LC/MS: (AA) ES+ 356

Example 46 Synthesis of4-(4-chlorobenzyl)-2-(3,6-dihydro-2H-pyran-4-yl)-1,3-thiazole-5-carboxylicacid (Compound 100)

Step 1: Ethyl 2-bromo-4-(4-chlorophenyl)-3-oxobutanoate

In a 250 mL round bottomed flask, to a solution of ethyl4-(4-chlorophenyl)-3-oxobutanoate (4.04 g, 16.8 mmol) in methylenechloride (100 mL, 2000 mmol) was added N-bromosuccinimide (3.13 g, 17.6mmol) and the mixture was stirred for 3 h at room temperature. Reactionwas quenched via addition of a 10% aqueous solution of NaHSO₃ (50 mL),and the resulting biphasic mixture was vigorously stirred for 15minutes. The reaction mixture was transferred to a reparatory funnel,the layers were separated, and the aqueous layer was extracted withCH₂Cl₂ (30 mL). The combined organic layers were washed with a saturatedaqueous solution of NaHCO₃ (50 mL), dried over anhydrous MgSO₄,filtered, and concentrated in vacuo to afford ethyl2-bromo-4-(4-chlorophenyl)-3-oxobutanoate (5.23 g, yield 97.5%) as ayellow oil that was used without further purification. LC/MS (FA)ES-317, 319, 321.

Step 2: Ethyl 2-amino-4-(4-chlorobenzyl)-1,3-thiazole-5-carboxylate

In a 100 mL round bottomed flask, to a solution of ethyl2-bromo-4-(4-chlorophenyl)-3-oxobutanoate (990 mg, 3.1 mmol) inisopropyl alcohol (20 mL, 300 mmol) was added thiourea (590 mg, 7.8mmol) and the resulting mixture was stirred at reflux for 16 hours. Themixture was allowed to cool to room temperature and then concentratedunder reduced pressure. The residue was suspended in EtOAc (50 mL) andthen washed with a saturated aqueous solution of NaHCO₃ (50 mL), brine(50 mL). The resulting organic layer was dried over anhydrous MgSO₄,filtered, and concentrated to afford ethyl2-amino-4-(4-chlorobenzyl)-1,3-thiazole-5-carboxylate (900 mg,yield>99%) as a yellowish solid that was used without furtherpurification. LC/MS (FA) ES+ 297, 299.

Step 3: Ethyl 2-bromo-4-(4-chlorobenzyl)-1,3-thiazole-5-carboxylate

In a 250 mL round bottomed flask, to a solution of ethyl2-amino-4-(4-chlorobenzyl)-1,3-thiazole-5-carboxylate (786 mg, 2.65mmol) in acetonitrile (75 mL, 1400 mmol) was added copper(II) bromide(963 mg, 4.31 mmol). The suspension was stirred at room temperature for15 minutes to afford a green solution. To the mixture was addedtert-butyl nitrite (0.630 mL, 5.30 mmol) and the reaction was thenheated with stirring at 70° C. for 1.5 hours. The reaction mixture wasallowed to cool to room temperature and then concentrated under reducedpressure. The residue was purified by column chromatography (80 gramcolumn, gradient elution 10% to 50% EtOAc/hexanes) to afford ethyl2-bromo-4-(4-chlorobenzyl)-1,3-thiazole-5-carboxylate (820 mg; yield86%) as a yellow syrup. LC/MS (FA) ES+ 360, 362, 364; ¹H NMR (400 MHz,CDCl₃) δ 7.33-7.20 (m, 4H), 4.44 (s, 2H), 4.34 (dd, J=7.1, 7.1, 2H),1.36 (dd, J=7.1, 7.1, 3H).

Step 4:Ethyl-4-(4-chlorobenzyl)-2-(3,6-dihydro-2H-pyran-4-yl)-1,3-thiazole-5-carboxylate

A mixture of ethyl 2-bromo-4-(4-chlorobenzyl)-1,3-thiazole-5-carboxylate(289 mg, 0.802 mmol), tributyl(3,6-dihydro-2H-pyran-4-yl)stannane (332mg, 0.890 mmol), tetrakis(triphenylphosphine)palladium(0) (46.4 mg,0.0401 mmol), lithium chloride (1.20E2 mg, 2.82 mmol) and copper(I)iodide (45.8 mg, 0.241 mmol) in dry 1,4-dioxane (6.26 mL, 80.2 mmol) wasdegassed by vacuum and backfilling with argon four times, and thenheated under argon at reflux for 3 hours. The mixture was filtered thruCelite, washing with 10% MeOH in DCM. Volatiles were removed in vacuo,and the residue was adsorbed to silica gel by concentrating a DCMsolution to which silica gel had been added. Column chromatography(gradient elution, 0 to 20% EA in hexanes) affordedethyl-4-(4-chlorobenzyl)-2-(3,6-dihydro-2H-pyran-4-yl)-1,3-thiazole-5-carboxylate(113 mg, 38.9%) as a white solid. ¹H NMR (300 MHz, DMSO) δ 7.35-7.31 (m,2H), 7.27-7.23 (m, 2H), 6.86-6.83 (m, 1H), 4.40 (s, 2H), 4.29 (q, J=6.9,2H), 4.25-4.22 (m, 2H), 3.78 (t, J=5.4, 2H), 2.51-2.46 (m, 2H), 1.27 (t,J=6.9 Hz, 3H).

Step 5:4-(4-chlorobenzyl)-2-(3,6-dihydro-2H-pyran-4-yl)-1,3-thiazole-5-carboxylicacid (Compound 100)

In a round bottom flask equipped with a stir bar, a solution of ethyl4-(4-chlorobenzyl)-2-(3,6-dihydro-2H-pyran-4-yl)-1,3-thiazole-5-carboxylate(109 mg, 0.300 mmol) in tetrahydrofuran (3.33 mL, 41.1 mmol) andmethanol (1.67 mL, 41.1 mmol) was treated with lithium hydroxide (1.0Min water, 2.40 mL, 2.40 mmol). The mixture was stirred at roomtemperature overnight. pH was adjusted to ˜3 via addition of 1N aqueousHCl solution, and the reaction was then diluted with EtOAc andtransferred to reparatory funnel. The layers were separated, and theaqueous layer was extracted 2× with EtOAc. Combined organic layers werewashed with brine, dried over Na₂SO₄, filtered, and concentrated invacuo. Column chromatography (gradient elution, 0 to 10% MeOH in DCM)afforded4-(4-chlorobenzyl)-2-(3,6-dihydro-2H-pyran-4-yl)-1,3-thiazole-5-carboxylicacid (100) (53 mg, yield 53% as a white powder. LCMS: (FA) ES+ 336; ¹HNMR (400 MHz, DMSO) δ 13.52 (bs, 1H), 7.35-7.31 (m, 2H), 7.27-7.23 (m,2H), 6.82-6.79 (m, 1H), 4.40 (s, 2H), 4.24-4.22 (m, 2H), 3.77 (t, J=5.4,2H), 2.50-2.45 (m, 2H).

Example 47 Synthesis of3-[amino(4-chlorophenyl)methyl]-4-cyano-5-(morpholin-4-yl)thiophene-2-carboxylicacid hydrochloride (Compound 113)

Step 1: N-[(E)-(4-chlorophenyl)methylene]-2-methylpropane-2-sulfinamide

To a solution of 4-chlorobenzaldehyde (2.88 g, 20.5 mmol),(S)-(−)-2-methyl-2-propanesulfinamide (1.40 g, 11.6 mmol), and(R)-(+)-2-methyl-2-propanesulfinamide (1.40 g, 11.6 mmol) in anhydroustetrahydrofuran (30.0 mL) under nitrogen atmosphere was added titaniumtetraisopropoxide (6.00 mL, 20.3 mmol) dropwise. The clear solution wasstirred at room temperature for 3 hours. Methylene chloride (200 mL) andwater (2.0 mL) were added and the mixture was stirred at roomtemperature for 1 hour. The suspension was filtered through Celite andwashed with DCM. The filtrate was concentrated in vacuo and purified bycolumn chromatography (gradient elution: 0-20% EtOAc/hexane) to affordN—[(E)-(4-chlorophenyl)methylene]-2-methylpropane-2-sulfinamide (3.93 g,yield 78.7%). LCMS: (FA) ES+ 244; ¹H NMR (400 MHz, CDCl₃) δ 8.55 (s,1H), 7.78-7.80 (d, 2H, J=8.53 Hz), 7.44-7.47 (d, 2H, J=8.53 Hz), 1.26(s, 9H).

Step 2:3-{[tert-butylsulfinyl)amino](4-chlorophenyl)methyl}-4-cyano-5-(morpholin-4-yl)thiophene-2-carboxylicacid

4-cyano-3-iodo-5-morpholin-4-ylthiophene-2-carboxylic acid (1.44 g, 3.96mmol, prepared as in WO2009/154741) was suspended in anhydroustetrahydrofuran (80.0 mL, 986 mmol), sonicated under nitrogen atmospherefor 10 min, and cooled in an acetone-dry ice bath for 10 minutes.Phenyllithium (1.8M in n-butyl ether, 8.81 mL, 15.9 mmol) was addeddropwise over 7 minutes. The suspension was stirred with cooling for 5minutes, at which point the cooling bath was removed and the suspensionwas stirred without cooling for 7 minutes. Reaction mixture was recooledin an acetone-dry ice bath for 10 minutes, at which point a solution ofN—[(E)-(4-chlorophenyl)methylene]-2-methylpropane-2-sulfinamide (2.91 g,11.9 mmol) in anhydrous tetrahydrofuran (20.0 mL, 246 mmol) was addeddropwise over 8 minutes, and the mixture was stirred with cooling for 30minutes. The mixture was quenched with methanol (5.0 mL, 120 mmol) andthen acetic acid (1.0 mL, 18 mmol), and allowed to warm to roomtemperature. The volatiles were removed in vacuo, and the residue wasdiluted with water and EtOAc. The layers were separated, and the aqueouslayer was extracted with 2×EtOAc. The combined organic layers werewashed with water and brine, dried over Na₂SO₄, filtered, andconcentrated in vacuo. Purification via column chromatography (gradientelution: AcOH/MeOH/DCM, 0/0/100 to 0.5/4.5/95) afforded3-{[(tert-butylsulfinyl)amino](4-chlorophenyl)methyl}-4-cyano-5-(morpholin-4-yl)thiophene-2-carboxylicacid as a mixture of diastereomers. Major diastereomer: 1.19 g, yield62.2%. (FA) ES+ 482; ES− 480; ¹H NMR (400 MHz, CDCl₃) δ 7.31-7.33 (m,2H), 7.15-7.17 (m, 2H), 6.14 (br s, 2H), 3.87-3.89 (m, 4H), 3.60-3.63(m, 4H), 1.21 (s, 9H). Minor diastereomer: (0.292 g, yield 15.3%). (FA)ES+ 482; ES− 480; ¹H NMR (400 MHz, CDCl₃) δ 7.26-7.34 (m, 4H), 6.29-6.38(m, br, 2H), 3.84-3.86 (m, 4H), 3.56-3.60 (m, 4H), 1.35 (s, 9H).

Step 3:3-[amino(4-chlorophenyl)methyl]-4-cyano-5-(morpholin-4-yl)thiophene-2-carboxylicacid hydrochloride (Compound 113)

To a solution of3-{[(tert-butylsulfinyl)amino](4-chlorophenyl)methyl}-4-cyano-5-(morpholin-4-yl)thiophene-2-carboxylicacid (1.46 g, 3.03 mmol) in methylene chloride (25.0 mL) was slowlyadded hydrochloric acid (4M in 1,4-dioxane, 15.0 mL), and the resultantsuspension was stirred at room temperature for 1 hour. The suspensionwas filtered through a fine frit funnel. The collected solid was washedwith DCM and dried in vacuo to afford3-[amino(4-chlorophenyl)methyl]-4-cyano-5-(morpholin-4-yl)thiophene-2-carboxylicacid hydrochloride (113) (1.10 g, yield 86.5%) as a white powder. LCMS:(FA) ES+ 378; ES− 376; ¹H NMR (400 MHz, CD3OD) δ 7.44-7.90 (m, 4H), 5.84(s, 1H), 3.81-3.84 (m, 4H), 3.64-3.67 (m, 4H).

Compounds in the following table are prepared from appropriate startingmaterials in a method analogous to that of Example 47.

291 LC/MS: (FA) ES+ 412, 413; ES− 410, 412 317 LC/MS: (FA) ES− 454, 456323 LCMS: (FA) ES+ 498; ES− 496 342 LC/MS: (FA) ES+ 516, 518; ES− 514,516 353 LC/MS: (FA) ES+ 420 354 LC/MS: (FA) ES+ 452 357 LC/MS: (FA) ES+394; ES− 392

Example 48 Synthesis of4-[1-(4-chlorophenyl)ethyl]-2-(morpholin-4-yl)-1,3-thiazole-5-carboxylicacid (Compound 121)

Step 1: Ethyl 4-(4-chlorophenyl)-3-oxopentanoate

In a round bottomed flask, to a suspension of2,2-dimethyl-1,3-dioxane-4,6-dione

(Meldrum's acid, 2.91 g, 20.2 mmol) in methylene chloride (11.3 mL, 177mmol) at −10° C. (internal temp) was added pyridine (4.00 mL, 49.5 mmol)over 10 minutes. To the resulting clear solution at −10° C., was addeddropwise a solution of 2-(4-chlorophenyl)propanoyl chloride (4.10 g,20.2 mmol) in methylene chloride (7.93 mL, 124 mmol) over 1 h. Thereaction mixture was then stirred for 1 h at −10° C., and then for 1hour at room temperature. The mixture was poured into hydrochloric acid(2.00M in water, 45.3 mL, 90.6 mmol) and ice, the layers were separated,and the aqueous phase was extracted with CH₂Cl₂. The combined organiclayers were washed with 1N HCl and brine, dried over anhydrous MgSO₄,filtered, and concentrated in vacuo. To the crude residue was addedethanol (39.6 mL, 679 mmol) and the mixture was heated at reflux (89degree bath temp) for 3 hours. After cooling to room temp, the volatileswere removed in vacuo. Residue was adsorbed onto silica using DCM andpurified via column chromatography (gradient elution: 0 to 20%EtOAc/hexanes to afford ethyl 4-(4-chlorophenyl)-3-oxopentanoate (2.94g, 92%) as a yellow oil. LCMS: (FA) ES+ 255; ¹H NMR (400 MHz, DMSO) δ7.34-7.30 (m, 2H), 7.17-7.13 (m, 2H), 4.16-4.09 (m, 2H), 3.90 (q, J=7.2,1H), 3.40 (d, J=15.6, 1H), 3.30 (d, J=15.6, 1H), 1.40 (d, J=6.8, 3H),1.23 (t, J=7.2, 3H).

Step 2: Ethyl4-[1-(4-chlorophenyl)ethyl]-2-(morpholin-4-yl)-1,3-thiazole-5-carboxylate

To a solution of ethyl 4-(4-chlorophenyl)-3-oxopentanoate (1.78 g, 6.99mmol) in methylene chloride (22.4 mL, 349 mmol) at 0° C. was addedsulfuryl chloride (566 uL, 6.99 mmol) and the mixture was stirredovernight at room temperature. The reaction was quenched with asaturated aqueous solution of NaHCO₃ and transferred to a separatoryfunnel. The layers were separated and the organic layer was washed withbrine, dried over anhydrous MgSO₄, filtered, and concentrated in vacuo.The resulting residue was used immediately without further purification.

In a round bottomed flask, to a solution of the crude residue from abovein isopropyl alcohol (50.3 mL, 657 mmol) was addedmorpholine-4-carbothioicacidamide (1.44 g, 9.86 mmol). The reactionmixture was heated with stirring at 90° C. for 90 minutes. Volatileswere removed in vacuo and the residue was redissolved in DCM and treatedwith saturated aqueous NaHCO₃ with stirring for 30 minutes. The layerswere separated, and the aqueous layer was extracted with DCM. Thecombined organic layers were washed with brine, dried over Mg₂SO₄,filtered, and concentrated in vacuo. Purification by columnchromatography (gradient elution: 0 to 25% EtOAc in hexanes) affordedethyl4-[1-(4-chlorophenyl)ethyl]-2-(morpholin-4-yl)-1,3-thiazole-5-carboxylate(1.45 g, 57.9%) as a white solid. LCMS: (FA) ES+ 381; ¹H NMR (400 MHz,DMSO) δ 7.41-7.37 (m, 2H), 7.24-7.21 (m, 2H), 5.12 (q, J=7.2, 1H),4.33-4.20 (m, 2H), 3.81-3.78 (m, 4H), 3.57-3.48 (m, 4H), 1.57 (d, J=6.8,3H), 1.33 (t, J=7.2, 3H).

Step 3:4-[1-(4-Chlorophenyl)ethyl]-2-(morpholin-4-yl)-1,3-thiazole-5-carboxylicacid (Compound 121)

To a solution of ethyl4-[1-(4-chlorophenyl)ethyl]-2-(morpholin-4-yl)-1,3-thiazole-5-carboxylate(1.42 g, 0.00373 mol) in tetrahydrofuran (30.2 mL, 0.373 mol) andmethanol (6.04 mL, 0.149 mol) was added sodium hydroxide (1.0N in water,29.8 mL, 0.0298 mol), and the resulting cloudy mixture was heated at 65°C. for 5 hours. The reaction was cooled to room temperature, dilutedwith water, and adjusted to pH 3.0 via addition of 1N aqueous HCl. Themixture was transferred to a separatory funnel and the layers separated.The aqueous layer was extracted with EtOAc, and the combined organiclayers were dried over MgSO₄, filtered, and concentrated in vacuo toafford4-[1-(4-chlorophenyl)ethyl]-2-(morpholin-4-yl)-1,3-thiazole-5-carboxylicacid (121) (1.21 g, yield 92%) as a white solid. LCMS: (FA) ES+ 353; ¹HNMR (400 MHz, DMSO) δ 12.70 (bs, 1H), 7.37-7.34 (m, 2H), 7.33-7.30 (m,2H), 5.09 (q, J=7.2, 1H), 3.69-3.76 (m, 4H), 3.48-3.39 (m, 4H), 1.49 (d,J=6.8, 3H).

Compounds in the following table are prepared from appropriate startingmaterials in a method analogous to that of Example 48.

304 LC/MS: (AA) ES+ 381, 383 332 LC/MS: (AA) ES+ 387, 389

Example 49 Synthesis of4-cyano-3-[(3,4-dichlorophenyl)(dimethylamino)methyl]-5-(morpholin-4-yl)thiophene-2-carboxylicacid (Compound 362)

Step 1:4-cyano-3-[(3,4-dichlorophenyl)(dimethylamino)methyl]-5-(morpholin-4-yl)thiophene-2-carboxylicacid

To a suspension of3-[amino(3,4-dichlorophenyl)methyl]-4-cyano-5-(morpholin-4-yl)thiophene-2-carboxylicacid.HCl (186.0 mg, 0.4145 mmol, prepared according to Example 6) inmethanol (8.09 mL, 0.101 mol) was added 10 M of formaldehyde in water(74.00 uL, 0.9119 mmol), and sodium cyanoborohydride (130 mg, 2.07mmol). Stirred at rt under argon for 16 hours. Added 10 M offormaldehyde in water soln (74.00 uL, 0.919 mmol) and sodiumcyanoborohydride (0.130 g, 2.07 mmol) and stirred at rt for 72 hours.Quenched reaction with saturated aqueous sodium bicarbonate solution,added EtOAc, separated layers, extracted again w/EtOAc, combinedorganics, washed organics with saturated sodium bicarbonate, brine,dried over Na₂SO₄, filtered, added Celite to filtrate, and concentratedin vacuo. Purification of dry load via silica gel column chromatography(gradient elution: 100% DCM to 8% MeOH in DCM) afforded racemic4-cyano-3-[(3,4-dichlorophenyl)(dimethylamino)methyl]-5-(morpholin-4-yl)thiophene-2-carboxylicacid (134 mg, 68%) as an off-white solid. LC/MS: (FA) 440, 442, 444; ¹HNMR (400 MHz, DMSO) δ 7.80-7.76 (m, 2H), 7.53 (dd, J=8.4, 2.1 Hz, 1H),5.26 (s, 1H), 3.74-3.64 (m, 4H), 3.53-3.38 (m, 4H), 2.76 (s, 3H), 2.42(s, 3H). Combined with another batch of 134 mg racemate for chiral HPLCto obtain pure enantiomers. Purified on IC 4.6×250 mm with 90/10/0.1HEX/ETOH/DEA 10 uL Injection at 1.0 mL/min for 70 min. CD AT 254 nm toobtain separated enantiomers as the diethylamine salts. Each compoundPeak1 and Peak2 were separately dissolved in water, acidified to pH of 2with aqueous 1N HCl solution, extracted w/EtOAc, 3×, combined organicsand washed w/brine, dried over Na₂SO₄, filtered, concentrated in vacuo,added water, freeze-dried, lyophilized overnight to recover parentcompound. Peak 1 (103 mg, tan solid, overall 27% yield) LC/MS: (FA) 440,442, 444; ¹H NMR (400 MHz, DMSO) δ 7.80-7.76 (m, 2H), 7.53 (dd, J=8.4,2.1 Hz, 1H), 5.26 (s, 1H), 3.74-3.64 (m, 4H), 3.53-3.38 (m, 4H), 2.76(s, 3H), 2.42 (s, 3H). Peak 2 (80 mg, beige solid, overall 20% yield)LC/MS: (FA) 440, 442, 444; ¹H NMR (400 MHz, DMSO) δ 7.80-7.76 (m, 2H)7.53 (dd, J=8.4, 2.1 Hz, 1H), 5.26 (s, 1H), 3.74-3.64 (m, 4H), 3.53-3.38(m, 4H), 2.76 (s, 3H), 2.42 (s, 3H).

Compounds in the following table are prepared from appropriate startingmaterials in a method analogous to that of Example 49.

336 LC/MS: (FA) ES+ 440, 442, 444 351 LC/MS: (FA) ES+ 406, 408

Example 50 Synthesis of4-cyano-5-[2-(hydroxymethyl)morpholin-4-yl]-3-(2-naphthylmethyl)thiophene-2-carboxylicacid (Compound 297)

Step 1: ethyl3-bromo-4-cyano-5-[2-(hydroxymethyl)morpholin-4-yl]thiophene-2-carboxylate

Ethyl 3,5-dibromo-4-cyanothiophene-2-carboxylate (0.360 g, 1.06 mmol),cesium carbonate (1.05 g, 3.21 mmol), 2-hydroxymethylmorpholine (137 mg,1.17 mmol), and tetrahydrofuran (4.5 mL, 36 mmol) were combined in a 15mL pressure vessel equipped with a stir bar. The vessel was sealed, andthe r×n was heated @ 90° C. with stiffing for 4 hours. The reaction wascooled to rt. The r×n was poured into water/saline. The reaction vesselwas washed out with additional water, then ethyl acetate, and these wereadded to the quench which was then transferred to a separatory funnel.The aqueous layer was extracted 3× with EtOAc. The extracts werecombined, washed with saline, dried over Na₂SO₄, filtered, added Celite,concentrated in vacuo, and dried on high vac 30 min. Purified dry loadvia silica gel chromatography (gradient elution: 0-60% EtOAc/hexanes) togive 163 mg solid (41% yield). ¹H NMR (400 MHz, DMSO) δ 4.91 (t, J=5.7Hz, 1H), 4.25 (q, J=7.1 Hz, 2H), 3.99-3.92 (m, 3H), 3.69-3.58 (m, 2H),3.50 (dt, J=10.5, 5.2 Hz, 1H), 3.41 (dt, J=11.5, 5.8 Hz, 1H), 3.37-3.27(m, 1H, under H2O peak), 3.15-3.08 (m, 1H), 1.26 (t, J=7.1 Hz, 3H).

Step 2: ethyl4-cyano-5-[2-(hydroxymethyl)morpholin-4-yl]-3-(2-naphthylmethyl)thiophene-2-carboxylateand4-cyano-5-[2-(hydroxymethyl)morpholin-4-yl]-3-(2-naphthylmethyl)thiophene-2-carboxylicacid

Bis(tri-t-butylphosphine)palladium(0) (16.44 mg, 0.03218 mmol) and ethyl3-bromo-4-cyano-5-[2-(hydroxymethyl)morpholin-4-yl]thiophene-2-carboxylate(161.0 mg, 0.4290 mmol) were combined in a dry round bottom flaskequipped with a stirbar and septum. Evacuated/refilled with argon 3×,then added 0.50 M solution of 2-naphthylmethylzinc bromide intetrahydrofuran (1.72 mL, 0.858 mmol) via a syringe to give a brownsoln. The reaction was stirred at rt for 5 minutes, then at 60° C. for1.5 h. Bis(tri-t-butylphosphine)palladium(0) (38.4 mg, 0.0751 mmol) and0.50 M solution of 2-naphthylmethylzinc bromide in tetrahydrofuran (1.29mL, 0.644 mmol) was added, degassed 2× and flushed w/argon, heated at60° C. 1 h. The reaction was cooled to rt, diluted with EtOAc, and thenquenched with sat. NH4Cl solution. Transferred quenched mixture to aseparatory funnel, separated layers, and extracted the aqueous layeronce more with EtOAc, combined organics, washed w/brine, dried overNa2SO4, filtered, and concentrated in vacuo. Added EtOAc and Celite,rotovapped, dried on high vac 30 min. Purified dry load onto 40 g ISCOcolumn (gradient elution: 0-55% EtOAc/hexanes) to obtain 119 mg yellowoil (64% yield). LC/MS (AA) ES+ 437.

Toethyl-4-cyano-5-[2-(hydroxymethyl)morpholin-4-yl]-3-(2-naphthylmethyl)thiophene-2-carboxylate(0.116 g, 0.266 mmol) in a rbf equipped with a stirbar was addedtetrahydrofuran (2.96 mL, 36.4 mmol) and 1.000 M of sodium hydroxide inwater (2.22 mL, 2.22 mmol) and methanol (1.48 mL, 36.5 mmol). Theresulting yellow mixture was stirred at rt for 16 h. The reaction wasquenched with the addition of 2.5 mL of 1N HCl in water to pH of 2, andadded EtOAc Transferred to separatory funnel, separated layers,extracted aquoeous 2×w/EtOAc, combined organics, washed w/brine, driedover Na2SO4, filtered, added Celite, and concentrate in vacuo. Purifieddry load via silica gel chromatography on 40 g ISCO column (gradientelution 0-20% MeOH/DCM) to give 66 mg white solid (61% yield). LC/MS(FA) ES+ 409; ES− 407; ¹H NMR (400 MHz, DMSO) δ 13.45 (br s, 1H),7.88-7.77 (m, 3H), 4.7 Hz, 3H), 7.69 (s, 1H), 7.51-7.42 (m, 3H), 4.87(s, 1H), 4.57-4.47 (m, 2H), 3.94-3.77 (m, 3H), 3.65-3.53 (m, 2H),3.60-3.52 (m, 1H), 3.47 (dd, J=11.3, 5.0 Hz, 1H), 3.37 (dd, J=11.3, 5.8Hz, 1H, overlaps with H₂O peak), 3.15 (td, J=12.1, 3.4 Hz, 1H),2.99-2.89 (m, 1H).

Example 10 Synthesis of2-morpholino-4-(naphthalen-2-ylmethyl)thiazole-5-sulfonamide (Compound329)

Step 1, Preparation of 2,4-dibromothiazole-5-sulfonyl chloride

To a flask containing chlorosulfonic acid (51.0 mL, 767 mmol) was added2,4-dibromothiazole (10.2 g, 42.0 mmol) with stiffing over 15 minutes.The resulting solution was heated to 150 degrees overnight. The reactionwas quenched by carefully and slowly pouring onto ice (500 mL). Theresulting precipitate was extracted with ethyl acetate (2×200 mL) andthe combined organic layers were washed with water, dried, andconcentrated in vacuo. The residue was purified by silica gelchromatography (ethyl acetate/hexane=0/100→15/85) to give 8.1 g (56%yield) of the title compound as a yellow oil which partially solidified.¹³C NMR (400 MHz, CDCl₃) δ: 145.04, 138.78, 131.81.

Step 2, Preparation of 2,4-dibromothiazole-5-sulfonamide

To a mixture of 2,4-dibromothiazole-5-sulfonyl chloride (3.17 g, 9.28mmol) in THF (51.4 mL) was added 33% aqueous NH₄OH (24.1 mL, 278 mmol)and the reaction was stirred at room temperature for 30 minutes. Thereaction was concentrated in vacuo and the residue was taken up in ethylacetate (100 mL) and water (100 mL). The aqueous layer was extractedwith ethyl acetate (50 mL) and the combined organic layers were washedwith water (50 mL) and brine (50 mL), then dried and concentrated invacuo. The residue was purified by silica gel chromatography (ethylacetate/DCM=0/100→20/80) to give 1.7 g (57% yield) of the titlecompound. as a white solid. LC/MS (FA) ES+ 321, 323, 325. ¹H NMR (400MHz, DMSO-d₆) δ: 8.33 (s, 2H).

Step 3, Preparation of 4-bromo-2-morpholinothiazole-5-sulfonamide

A mixture of 2,4-dibromothiazole-5-sulfonamide (0.515 g, 1.60 mmol),morpholine (0.153 mL, 1.76 mmol), THF (4.22 mL) and cesium carbonate(1.56 g, 4.80 mmol) in a sealed tube was heated to 80 degrees for 4hours. The cooled reaction was concentrated in vacuo and the residue wastaken up in ethyl acetate (50 mL) and water (25 mL). The layers wereseparated and the organic layer was washed with water (15 mL), dried andconcentrated in vacuo. The residue was purified by silica gelchromatography (ethyl acetate/DCM=0/100→50/50) to give 230 mg (44%yield) of the title compound as a white solid. LC/MS (FA) ES+ 328, 330.¹H NMR (400 MHz, DMSO-d₆) δ: 7.76 (s, 2H), 3.69-3.66 (m, 4H), 3.43-3.40(m, 4H).

Step 4, Preparation of2-morpholino-4-(naphthalen-2-ylmethyl)thiazole-5-sulfonamide

To a dried flask was added 4-bromo-2-morpholinothiazole-5-sulfonamide(194 mg, 0.591 mmol), THF (4.79 mL), palladium(II) acetate (1.33 mg,0.00591 mmol) and dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine(4.85 mg, 0.0118 mmol). The mixture was stirred for 5 minutes, and a0.500 M solution of 2-napthylmethylzinc bromide in THF (4.14 mL, 2.04mmol) was then added dropwise over 30 minutes. The reaction was stirredat room temperature for 1 hour and quenched with saturated ammoniumchloride (10 mL). The reaction was extracted with ethyl acetate (2×25mL) and the combined organic layers were washed with water (15 mL),dried and concentrated in vacuo. The residue was purified by silica gelchromatography (ethyl acetate/DCM=0/100→40/60) which gave a mixture ofthe desired product with residual4-bromo-2-morpholinothiazole-5-sulfonamide. This material was purifiedby preparative reverse phase chromatography to give 51 mg (22% yield) ofthe title compound as a white solid. LC/MS (FA) ES+ 390. ¹H NMR (400MHz, DMSO-d₆) δ: 7.85-7.77 (m, 4H), 7.71 (bs, 2H), 7.50-7.42 (m, 3H),4.25 (s, 2H), 3.64-3.61 (m, 4H), 3.35-3.32 (m, 4H).

Example 51 Synthesis of4-cyano-3-[1-(3,4-dichlorophenyl)but-3-en-1-yl]-5-(morpholin-4-yl)thiophene-2-carboxylate(Compound 355)

Step 1: To a solution of N,N-diisopropylamine (1.79 mL, 12.8 mmol) intetrahydrofuran (10.0 mL, 123 mmol) was added 2.50 M of n-butyllithiumin hexane (4.68 mL, 11.7 mmol) dropwise at 0° C. The solution wasstirred under an atmosphere of Nitrogen for 10 min, and then cooled to−78° C. A solution of methyl 3,4-dichlorophenylacetate (2.27 g, 10.4mmol) in tetrahydrofuran (10.0 mL) was added to the LDA solutiondropwise via cannula. After 10 min of stirring, the reaction was warmedto 0° C. for 1 hr. The solution was cooled back to −78° C., and allylbromide (2.24 mL, 25.9 mmol) was added in one portion. In 10 min, thereaction was warmed back to 0° C. After 1 hr of stirring, the reactionwas quenched with NH₄Cl sat soln and extracted with EtOAc (×3). Thecombined organic layer was dried and concentrated to provide an orangeoil. Further purification on a silica gel column (gradient elution,0-10% EtOAc/hexanes) provided methyl 2-(3,4-dichlorophenyl)pent-4-enoateas a colorless oil (2.47 g, 92.0% yield). ¹H NMR (400 MHz, CDCl₃) δ7.43-7.37 (m, 2H), 7.18-7.12 (dd, J=8.3, 2.1 Hz, 1H), 5.73-5.60 (ddt,J=17.1, 10.2, 6.8 Hz, 1H), 5.12-4.98 (m, 2H), 3.70-3.64 (s, 3H),3.63-3.55 (t, J=7.8 Hz, 1H), 2.85-2.71 (m, 1H), 2.55-2.43 (m, 1H).

Step 2: To a solution of methyl 2-(3,4-dichlorophenyl)pent-4-enoate(2.47 g, 9.53 mmol) in tetrahydrofuran (15.0 mL) was added a solution oflithium hydroxide monohydrate (2.00 g, 47.6 mmol) in water (15.0 mL).The mixture was vigorously stirred at rt for 12 hrs. The resultingmixture was acidified by addition of 12.0 M of hydrochloric acid inwater (3.97 mL, 47.6 mmol) at 0° C., and extracted with EtOAc (×3). Thecombined organic layer was dried and concentrated to provide2-(3,4-dichlorophenyl)pent-4-enoic acid as a yellow syrup (2.65 g,quantative). ¹H NMR (400 MHz, CDCl₃) δ 7.45-7.35 (m, 2H), 7.21-7.11 (dd,J=8.3, 2.1 Hz, 1H), 5.76-5.59 (ddt, J=17.0, 10.2, 6.8 Hz, 1H), 5.14-4.99(m, 2H), 3.65-3.56 (t, J=7.7 Hz, 1H), 2.88-2.74 (dt, J=14.8, 7.5 Hz,1H), 2.58-2.43 (dt, J=14.3, 6.9 Hz, 1H).

Step 3: To a soln of 2-(3,4-dichlorophenyl)pent-4-enoic acid (2.34 g,9.53 mmol) in methylene chloride (25.0 mL) was added oxalyl chloride(1.61 mL, 19.0 mmol) followed by N,N-dimethylformamide (73.8 uL, 0.953mmol) After 1 hr of stirring at rt, the solution was concentrated toprovide 2-(3,4-dichlorophenyl)pent-4-enoyl chloride as a yellow oil(2.70 g, quantative). ¹H NMR (400 MHz, CDCl₃) δ 7.49-7.42 (d, J=8.3 Hz,1H), 7.40-7.36 (d, J=2.2 Hz, 1H), 7.17-7.10 (dd, J=8.3, 2.2 Hz, 1H),5.73-5.57 (ddt, J=17.1, 10.2, 6.9 Hz, 1H), 5.15-5.06 (m, 2H), 4.06-3.97(t, J=7.6 Hz, 1H), 2.97-2.83 (m, 1H), 2.61-2.49 (m, 1H).

Step 4: To a solution of 2-(3,4-dichlorophenyl)pent-4-enoyl chloride(2.51 g, 9.53 mmol) and 3-morpholin-4-yl-3-thioxopropanenitrile (1.62 g,9.53 mmol) in acetonitrile (40.0 mL) in a 100 mL round bottom flask wasadded N,N-diisopropylethylamine (1.82 mL, 10.5 mmol), and the resultingdeep orange/red solution was stirred at room temp for 1 hr. To theresulting mixture was added N,N-diisopropylethylamine (4.15 mL, 23.8mmol) and then ethyl iodoacetate (1.24 mL, 10.5 mmol). The flask wasfitted with a reflux condenser and the reaction was heated to refluxover 48 hrs. The mixture was concentrated and distributed betweenNaHCO₃(aq) saturated solution and EtOAc. The aqueous layer was extractedwith EtOAc (×2). The combined org layer was washed with brine, dried,and concentrated to provide a dark syrup. Purification on a silica gelcolumn (gradient elution 3-30% EtOAc/hexanes) provided ethyl4-cyano-3-[1-(3,4-dichlorophenyl)but-3-en-1-yl]-5-(morpholin-4-yl)thiophene-2-carboxylate(704 mg, 15.9% yield). LCMS: (AA) ES+ 465, 467, 469; ¹H NMR (400 MHz,CDCl₃) δ 7.49-7.42 (m, 1H), 7.41-7.33 (m, 1H), 7.31-7.27 (m, 1H),5.82-5.66 (ddt, J=17.2, 10.1, 6.8 Hz, 1H), 5.62-5.50 (t, J=8.2 Hz, 1H),5.16-5.08 (dd, J=17.1, 1.6 Hz, 1H), 5.04-4.94 (dd, J=10.2, 1.5 Hz, 1H),4.35-4.27 (q, J=7.1 Hz, 2H), 3.86-3.78 (m, 4H), 3.59-3.48 (m, 4H),3.10-2.99 (h, J=6.9 Hz, 2H), 1.40-1.31 (m, 3H).

Step 5: To a solution of ethyl4-cyano-3-[1-(3,4-dichlorophenyl)but-3-en-1-yl]-5-(morpholin-4-yl)thiophene-2-carboxylate(0.211 g, 0.453 mmol) in tetrahydrofuran (8.00 mL) was added 1.000 M ofsodium hydroxide in water (10.0 mL) and methanol (4.00 mL). Theresulting mixture was stirred at room temp over 3 hrs. The volatileswere removed under reduced pressure, and the resulting mixture wasacidified with conc. HCl soln to pH˜2, and extracted with EtOAc (×3).The combined org layer was dried and concentrated to provide a purplesyrup. Purification of the crude mixture on HPLC (AA, reverse phase)provided4-cyano-3-[1-(3,4-dichlorophenyl)but-3-en-1-yl]-5-(morpholin-4-yl)thiophene-2-carboxylicacid as a white solid (63 mg, 31.8% yield). LCMS: (AA) ES− 391, 393,395; ¹H NMR (400 MHz, MeOD) δ 7.54-7.46 (d, J=1.6 Hz, 1H), 7.45-7.35 (d,J=8.4 Hz, 1H), 7.34-7.24 (dd, J=8.4, 1.6 Hz, 1H), 5.88-5.68 (m, 2H),5.16-5.05 (dd, J=17.1, 1.7 Hz, 1H), 5.00-4.92 (m, 1H), 3.82-3.71 (t,J=4.8 Hz, 4H), 3.51-3.40 (t, J=4.8 Hz, 4H), 3.05-2.95 (m, 2H).

Compounds in the following table are prepared from appropriate startingmaterials in a method analogous to that of Example 51.

307 LC/MS: (FA) ES− 412 308 LC/MS: (FA) ES− 413 321 LC/MS: (AA) ES+ 411,413 326 LC/MS: (AA) ES+ 411 345 LC/MS: (FA) ES− 395 349 LC/MS: (FA) ES−437 358 LC/MS: (FA) ES+ 399, 401 364 LC/MS: (FA) ES− 395 369 LC/MS: (AA)ES+ 411

Example 52 Synthesis of4-cyano-3-(isoquinolin-7-ylmethyl)-5-(morpholin-4-yl)thiophene-2-carboxylicacid (Compound 309)

Step 1: 5-Amino-4-cyano-3-methyl-thiophene-2-carboxylic acid ethyl ester

To a solution of 3-oxobutanoic acid, methyl ester (8.25 mL, 76.4 mmol),malononitrile (5.05 g, 76.4 mmol) and sulfur (2.45 g, 76.4 mmol) inanhydrous ethanol (100 mL, 2000 mmol) was added triethylamine (10.7 mL,76.8 mmol). The mixture was heated to reflux for 30 min. The mixture wascooled to room temperature. The resulted crystal was collected byfiltration and washed with MeOH, dried in vacuum to afford the product(9.25 g, yield 61.7%). LC/MS: (FA) ES− 195. ¹H NMR (400 MHz,d-chloroform) δ 5.13 (s, br, 2H), 3.82 (s, 3H), 2.52 (s, 3H).

Step 2 Methyl 5-bromo-4-cyano-3-methylthiophene-2-carboxylate

To a dark solution of Methyl5-amino-4-cyano-3-methylthiophene-2-carboxylate (6.65 g, 33.9 mmol) andcopper(II) bromide (15.1 g, 67.8 mmol) in anhydrous acetonitrile (260mL) was added slowly butyl nitrite (7.26 mL, 61.0 mmol) over 8 min. Themixture was stirred at room temperature for 70 min. The mixture wasconcentrated in rotavapor to give a black residue. The residue wasdissolved in DCM, filtered through Celite. The filtrate was rotavapedwith Celite. The Celite coated residue was dry loaded into a silica gelcolumn and chromatographed using EtOAc/hexane (0/100 to 10/90) to give awhite solid product (6.29 g, yield 71.4%). ¹H NMR (400 MHz,d-chloroform) δ 3.89 (s, 3H), 2.67 (s, 3H)

Step 3: Methyl4-cyano-3-methyl-5-(morpholin-4-yl)thiophene-2-carboxylate

A mixture of methyl 5-bromo-4-cyano-3-methylthiophene-2-carboxylate(6.29 g, 24.2 mmol), morpholine (2.53 g, 29.0 mmol) and cesium carbonate(15.8 g, 48.4 mmol) in anhydrous Tetrahydrofuran (110 mL) was heated toreflux for 19 hours, and then cooled to room temperature. The mixturewas filtered and washed with DCM. The filtrate was rotavaped withCelite. The coated Celite was dry loaded in a silica gel cartridge andchromatographed using MeOH/DCM (199) to give a white solid product (4.70g, yield 73%). LC/MS: (FA) ES⁺ 267. ¹H NMR (400 MHz, d-chloroform) δ3.85 (m, 4H), 3.82 (s, 3H), 3.58 (m, 4H), 2.56 (s, 3H).

Step 4: Methyl3-(bromomethyl)-4-cyano-5-(morpholin-4-yl)thiophene-2-carboxylate

To the solution of methyl4-cyano-3-methyl-5-(morpholin-4-yl)thiophene-2-carboxylate (0.500 g,1.88 mmol) in anhydrous methylene chloride (15 mL, 230 mmol) was added asolution of bromine (0.409 g, 2.56 mmol) in anhydrous methylene chloride(5.0 mL, 78 mmol). The mixture was stirred at room temperature for 4days. The mixture was evaporated under reduced pressure and dried invacuum to give a crude product that was used without furtherpurification (0.658 g, contained 3.4% starting material, yield 96.6%).LC/MS: (FA) ES⁺ 345, 347. ¹H NMR (400 MHz, d-chloroform) δ 4.83 (s, 2H),3.87 (s, 3H), 3.85 (m, 4H), 3.62 (m, 4H).

Step 5: Methyl4-cyano-3-(isoquinolin-7-ylmethyl)-5-(morpholin-4-yl)thiophene-2-carboxylate

A mixture of methyl3-(bromomethyl)-4-cyano-5-(morpholin-4-yl)thiophene-2-carboxylate (0.128g, 0.371 mmol), isoquinoline-7-boronic acid (101 mg, 0.584 mmol),tetrakis(triphenylphosphine)palladium(0) (21.4 mg, 0.0185 mmol) andcesium carbonate (0.242 g, 0.742 mmol) was suspended in 1,4-dioxane (8.0mL, 100 mmol) and Water (0.60 mL, 33 mmol) under N₂ atmosphere in a 20mL vial. The vial was capped and heated to 90° C. for 1 hour. Themixture was cooled to room temperature and concentrated in vacuum. Theresidue was suspended in DCM and filtered over a celite pad. Thefiltrate was chromatographed in a silica gel column using MeOH/DCM(0/100 to 3/97) to afford a solid product (103 mg, 66.4%). LC/MS: (FA)ES⁺ 394. ¹H NMR (400 MHz, d-chloroform) δ 9.20 (s, 1H), 8.47 (d, J=5.77Hz, 1H), 7.87 (s, 1H), 7.73 (d, J=5.77 Hz, 1H), 7.60 (d, J=5.77 Hz, 1H),7.44-7.48 (m, 1H), 4.60 (s, 2H), 3.86 (s, 3H), 3.84 (m, 4H), 3.59 (m,4H).

Step 6:4-cyano-3-(isoquinolin-7-ylmethyl)-5-(morpholin-4-yl)thiophene-2-carboxylicacid

To the solution of methyl4-cyano-3-(isoquinolin-7-ylmethyl)-5-(morpholin-4-yl)thiophene-2-carboxylate(0.103 g, 0.246 mmol) in tetrahydrofuran (15.0 mL, 185 mmol) was added1.00 M of sodium hydroxide in water (3.80 mL, 3.80 mmol), followed bywater (4.0 mL, 220 mmol) and methanol (4.0 mL, 99 mmol). The homogeneoussolution was stirred at room temperature for 18 hours. Acetic acid (270mg, 4.5 mmol) was added and the mixture was concentrated in rotavapor.The residue was dissolved in DCM-MeOH and then concentrated with celite.The mixture was loaded in a cartridge and chromatographed in a silicagel column using AcOH/MeOH/DCM (0/0/100 to 0.5/4.5/95) to afford a whitesolid product (56.5 mg, yield 60.3%). LC/MS: (FA) ES⁺ 380; ES⁻ 378. ¹HNMR (400 MHz, d-chloroform) δ 9.23 (s, 1H), 8.45 (d, J=5.77 Hz, 1H),7.90 (d, J=8.53 Hz, 1H), 7.84 (s, 1H), 7.76 (d, J=5.77 Hz, 1H), 7.65(dd, J=8.53, 1.76 Hz, 1H), 4.53 (s, 2H), 3.72 (m, 4H), 3.52 (m, 4H).

Compounds in the following table are prepared from appropriate startingmaterials in a method analogous to that of Example 52.

287 LC/MS: (AA) ES− 395 293 LC/MS: (AA) ES− 395 295 LC/MS: (AA) ES− 395301 LC/MS: (AA) ES+ 409 305 LC/MS: (FA) ES− 381 311 LCMS: (FA) ES+ 385;ES− 383 312 LC/MS: (FA) ES+ 386, 388; ES− 384, 386 315 LC/MS: (FA) ES+397 324 LC/MS: (AA) ES− 395 330 LC/MS: (FA) ES+ 382; ES− 380 343 LC/MS:(AA) ES− 395 359 LC/MS: (FA) ES+ 402, 404; ES− 401, 403 361 LC/MS: (AA)ES+ 409

Example 53 Synthesis Example 3: Synthesis of4-cyano-3-[methoxy(2-naphthyl)methyl]-5-(morpholin-4-yl)thiophene-2-carboxylicacid (Compound 368)

Step 1:4-cyano-3-[hydroxy(2-naphthyl)methyl]-5-(morpholin-4-yl)thiophene-2-carboxylicacid

A solution of 3-bromo-4-cyano-5-morpholinothiophene-2-carboxylic acid(5.50 g, 17.3 mmol) and 2-naphthalenecarboxaldehyde (8.12 g, 52.0 mmol)in tetrahydrofuran (550 mL) was cooled at −78° C. for 10 min, resultingin a white suspension. 2.5 M of n-butyllithium in hexane (27.7 mL, 69.4mmol) was added dropwise, resulting in an orange solution. The solutionwas stirred at −78° C. for 10 min, then the cold bath was removed andthe orange solution was stirred at ambient temperature for 40 minutes.The solution was quenched by the addition of methanol (21 mL) and aceticacid (3.9 mL), and the resulting mixture was let to warm up to rt O/N.The mixture was combined with a previous run on 2.86 g scale of thecarboxylic acid, concentrated in vacuo, and azeotroped with toluene(2×50 mL). The crude solid was dissolved in MeOH, added Celite,rotavapped, dried on high vac O/N. The crude product was purified usingdry load via silica gel chromatography on 330 g ISCO column (gradientelution 0-20% of (10% AcOH in MeOH) in DCM) to give 15.2 g solidcontaining 37 wt % AcOH, for overall 92% yield. LC/MS (AA) ES− 393; ¹HNMR (400 MHz, DMSO) δ 10.86 (d, J=9.9 Hz, 1H), 7.86-7.81 (m, 4H), 7.70(dd, J=8.6, 1.6 Hz, 1H), 7.51-7.42 (m, 2H), 5.69 (d, J=9.4 Hz, 1H),3.73-3.68 (m, 4H), 3.39-3.33 (m, 4H).

Step 2: methyl4-cyano-3-[methoxy(2-naphthyl)methyl]-5-(morpholin-4-yl)thiophene-2-carboxylate

To a round bottom flask was added silver(I) oxide (56.15 g, 0.2423 mol),4-cyano-3-[hydroxy(2-naphthyl)methyl]-5-(morpholin-4-yl)thiophene-2-carboxylicacid (15.17 g, 0.02423 mol), and N,N-dimethylformamide (66.2 mL),followed by methyl iodide (53.7 mL, 0.863 mol). Added another 10 mL DMF,sonicated to suspend/mix all solid. The reaction mixture was stirred atroom temperature for 26 hours, then was diluted with EtOAc, filteredthrough a pad of Celite, concentrated filtrate in vacuo, azeotropedw/toluene (10×10 mL), DCM (20 mL), dried on high vacuum pump. The rudematerial was used directly in the next step. LC/MS (AA) ES+ 423, ES+Na+445; ¹H NMR (400 MHz, DMSO) δ 7.97 (s, 1H), 7.91-7.86 (m, 3H),7.53-7.48 (m, 3H), 6.62 (s, 1H), 3.85 (s, 3H), 3.72-3.69 (m, 4H),3.52-3.50 (m, 4H), 3.43 (s, 3H).

Step 3:4-cyano-3-[methoxy(2-naphthyl)methyl]-5-(morpholin-4-yl)thiophene-2-carboxylicacid

To methyl4-cyano-3-[methoxy(2-naphthyl)methyl]-5-(morpholin-4-yl)thiophene-2-carboxylate(10.56 g, 25 mmol) in a round bottom flask equipped with a stirbar wasadded tetrahydrofuran (278 mL) and 1.000 M of sodium hydroxide in water(208 mL, 208 mmol). Methanol (139 mL) was added to the mixture, and theresulting yellow mixture was stirred at room temperature for 16 h. Thereaction mixture was quenched by the addition of 1N HCl aqueous solutionto adjust the pH to 2 and EtOAc was added. The mixture was transferredto a separatory funnel, separated layers, extracted aqueous 2× w/EtOAc,combined organics, washed w/brine, dried over Na₂SO₄, filtered, addedcelite, rotavapped, dried on high vacuum for 45 min. The crude materialwas purified using a dry load on 330 g silica gel ISCO column (gradientelution: 0-20% MeOH/DCM) to obtain the product as an impure beige solid(9.8 g). Took 2 g, redissolved in DCM, added Celite, rotovapped, driedon high vac 45 min. Repurified this portion of product on 120 g ISCOsilica gel column (gradient elution: 0-12% MeOH/DCM) to obtain 2.0 gbeige foam product (racemate). LC/MS (FA) ES− 407; ¹H NMR (400 MHz,DMSO) δ 13.57 (s, 1H), 7.96 (s, 1H), 7.89-7.86 (m, 3H), 7.53-7.46 (m,3H), 6.68 (s, 1H), 3.73-3.67 (m, 4H), 3.50-3.45 (m, 4H), 3.43 (s, 3H).Enantiomeric separation of the enantiomers was performed by chiral HPLCon CHIRALPAK IC 4.6×250 mm with 855100.1% HEX/IPA/ETOH/DEA 10 uLInjection at 1.0 mL/min for 50 min.

Step 4:4-cyano-3-[methoxy(2-naphthyl)methyl]-5-(morpholin-4-yl)thiophene-2-carboxylicacid

4-cyano-3-[methoxy(2-naphthyl)methyl]-5-(morpholin-4-yl)thiophene-2-carboxylicacid (313.0 mg, 0.7663 mmol) was suspended in ethanol (7.159 mL, 122.6mmol) and water (2.071 mL, 114.9 mmol) at room temperature. 1.030 M ofsodium hydroxide in water (744.0 uL, 0.7663 mmol) was added slowly andthe resulting solution was stirred for 10 min. The organic solvent wasremoved in vacuo. Added 40 ml water, freeze-dried, and lyophilized overnight to give 322 mg amber solid (98% yield). LC/MS (FA) ES− 407.5; ¹HNMR (400 MHz, DMSO) δ 7.99 (s, 1H), 7.88-7.76 (m, 3H), 7.61 (dd, J=8.6,1.3 Hz, 1H), 7.50-7.42 (m, 2H), 7.24 (s, 1H), 3.68-3.65 (m, 4H), 3.37(s, 3H), 3.26-3.33 (m, 4H).

Compounds in the following table are prepared from appropriate startingmaterials in a method analogous to that of Example 53.

337 LC/MS: (FA) ES− 407

Example 54 Synthesis of Ethyl4-cyano-5-(morpholin-4-yl)-3-[1-(2-naphthyl)ethyl]thiophene-2-carboxylate(Compound 367)

Step 1: A 1 L flask was charged with a big egg-shape stirring bar andethyl4-cyano-5-morpholin-4-yl-3-(2-naphthylmethyl)thiophene-2-carboxylate(14.5 g, 35.7 mmol). To the flask was added N,N-dimethylformamide (240mL) and the mixture was evacuated and purged with nitrogen (×3). To theflask was added tetrahydrofuran (60 mL), and the mixture was stirreduntil it became a clear yellow solution. The solution was cooled to˜−25° C. in a dry ice-acetone bath (the temperature was activelycontrolled by slow addition of dry ice between −30˜−40° C.). 1 M ofPotassium tert-butoxide in tetrahydrofuran (42.8 mL) was added dropwiseover 3 min. The mixture turned deep purple immediately. After theaddition the mixture was stirred for 10 min at this temperature. Methyliodide (11.1 mL, 178 mmol) was added over 1 min. By the end of additionthe mixture turned light red. After stirring the resulting mixture at 0°C. for 10 min, the reaction was quenched by addition of 10 mL of water.All volatiles were removed under reduced pressure and the resultingmixture was distributed between brine and EtOAc. The aqueous layer wasextracted with EtOAc (×2). The combined organic layers were washed with10% LiCl(aq) soln (×3), then brine, dried, and concentrated to provide ayellow syrup. Purification on a silica gel column (gradient elution5-20% EtOAc/hexanes) provided Ethyl4-cyano-5-(morpholin-4-yl)-3-[1-(2-naphthyl)ethyl]thiophene-2-carboxylateas a white solid (11.8 g, 78.7% yield). LCMS: (AA) ES+ 421; ¹H NMR (400MHz, CDCl₃) δ 7.90-7.82 (m, 2H), 7.82-7.70 (dd, J=15.4, 8.1 Hz, 2H),7.50-7.37 (m, 3H), 5.82-5.67 (q, J=7.3 Hz, 1H), 4.40-4.25 (qd, J=6.1,5.0, 3.1 Hz, 2H), 3.86-3.72 (t, J=4.8 Hz, 4H), 3.54-3.44 (t, J=4.8 Hz,4H), 1.95-1.85 (d, J=7.3 Hz, 3H), 1.42-1.31 (t, J=7.1 Hz, 3H).

Step 2: Ethyl4-cyano-5-(morpholin-4-yl)-3-[1-(2-naphthyl)ethyl]thiophene-2-carboxylate(13.3 g, 31.6 mmol) in tetrahydrofuran (200 mL) and methanol (150 mL)was stirred until the mixture turned into a clear solution. To thesolution was added 1.000 M sodium hydroxide in water (158 mL). Theresulting turbid mixture was vigorously stirred at rt for 12 h. Thevolatiles were removed under reduced pressure, and the resulting aqueoussolution was acidified by addition of 12.0 M of hydrochloric acid inwater (15.9 mL, 191 mmol) at 0° C., and then extracted with EtOAc (×3).The combined organic layers were washed with 1M HCl soln, dried, andconcentrated to provide4-cyano-5-(morpholin-4-yl)-3-[1-(2-naphthyl)ethyl]thiophene-2-carboxylicacid as a white solid (12.1 g, 97.5% yield). 250 mg of the racemicmixture was purified on chiral prep HPLC to provide each enantiomer (115mg each, >95% cc) (OJ column, elution with 85/5/10/0.1%hexane/iPrOH/EtOH/Et₂NH). LCMS: (AA) ES+ 393; ¹H NMR (400 MHz, MeOD) δ7.85-7.76 (m, 3H), 7.76-7.71 (d, J=8.6 Hz, 1H), 7.49-7.38 (m, 2H),7.38-7.29 (dd, J=8.5, 1.7 Hz, 1H), 5.90-5.74 (q, J=7.3 Hz, 1H),3.82-3.69 (m, 4H), 3.52-3.43 (dd, J=5.8, 4.0 Hz, 4H), 1.91-1.80 (d,J=7.3 Hz, 3H).

Step 3: The active enantiomer4-cyano-5-(morpholin-4-yl)-3-[1-(2-naphthyl)ethyl]thiophene-2-carboxylicacid (780 mg, 1.99 mmol) was suspended in ethanol (10.0 mL, 171 mmol).To the mixture was added 1.030 M of sodium hydroxide in water (2.00 mL,2.06 mmol). The mixture was swirled and sonicated until it turnedhomogeneous. The solution was concentrated to provide4-cyano-5-(morpholin-4-yl)-3-[1-(2-naphthyl)ethyl]thiophene-2-carboxylicacid.Na as a yellow solid (785 mg, 95% yield). LCMS: (AA) ES+ 393; ¹HNMR (400 MHz, MeOD) δ 7.85-7.72 (m, 3H), 7.72-7.66 (d, J=8.6 Hz, 1H),7.45-7.30 (ddd, J=12.6, 4.9, 2.2 Hz, 3H), 6.20-6.06 (q, J=7.0 Hz, 1H),3.81-3.70 (t, J=4.8 Hz, 4H), 3.40-3.32 (t, J=4.8 Hz, 4H), 1.88-1.78 (d,J=7.4 Hz, 3H).

Compounds in the following table are prepared from appropriate startingmaterials in a method analogous to that of Example 54.

306 LC/MS: (FA) ES+ 423 313 LC/MS: (FA) ES+ 423 322 LC/MS: (FA) ES+ 425333 LC/MS: (AA) ES+ 393 346 LC/MS: (FA) ES+ 369 363 LC/MS: (FA) ES+ 423365 LC/MS: (FA) ES+ 425 366 LC/MS: (AA) ES− 409, 411, 413

Example 55 Synthesis of4-(54(1H-tetrazol-5-yl)methyl)-4-(3,4-dichlorobenzyl)thiazol-2-yl)morpholine(Compound 350)

Step 1, Preparation of(4-(3,4-dichlorobenzyl)-2-morpholinothiazol-5-yl)methanol

To a solution of ethyl4-(3,4-dichlorobenzyl)-2-morpholinothiazole-5-carboxylate (4.92 g, 12.2mmol) in THF (100 mL) was added a 2.00 M solution of LAH in THF (12.9mL, 25.8 mmol) and the resulting solution was stirred for 2 hours atroom temperature. The reaction was quenched by adding saturated NH₄Cl(26 mL) followed by 1M HCl (26 mL). Water (100 mL) and ethyl acetate(200 mL) were then added. The layers were separated and the organiclayer was washed with brine (50 mL). The organic layer was dried andconcentrated in vacuo. The residue was purified by silica gelchromatography (ethyl acetate/DCM=0/100→100/0) to give 2.87 g (65%yield) of the title compound. as a white solid. LC/MS (FA) ES+ 359, 361.¹H NMR (400 MHz, CDCl₃) δ: 7.34-7.31 (m, 2H), 7.09 (dd, 1H, J=6.0, 2.0Hz), 4.66 (d, 2H, J=1.2 Hz), 3.84 (s, 2H), 3.79-3.77 (m, 4H), 3.42-3.39(m, 4H).

Step 2, Preparation of2-(4-(3,4-dichlorobenzyl)-2-morpholinothiazol-5-yl)acetonitrile

To a solution of(4-(3,4-dichlorobenzyl)-2-morpholinothiazol-5-yl)methanol (1.19 g, 3.31mmol) in THF (58.6 mL) was added acetone cyanohydrin (0.454 mL, 4.97mmol), 1,1′-(azodicarbonyl)dipiperidine (1.67 g, 6.62 mmol) andtributylphosphine (1.65 mL, 6.62 mmol) and the reaction was stirred for3 hours at room temperature. The reaction was concentrated in vacuo. Theresidue was purified by silica gel chromatography (ethylacetate/DCM=0/100→20/80) to give 551 mg (45% yield) of the titlecompound as a beige solid. LC/MS (FA) ES+ 368, 370. ¹H NMR (400 MHz,CDCl₃) δ: 7.35 (d, 1H, J=6.0 Hz), 7.32 (d, 1H, J=2.0 Hz), 7.07 (dd, 1H,J=6.0, 2.0 Hz), 3.82 (s, 2H), 3.80-3.77 (m, 4H), 3.66 (s, 2H), 3.42-3.40(m, 4H).

Step 3, Preparation of4-(54(1H-tetrazol-5-yl)methyl)-4-(3,4-dichlorobenzyl)thiazol-2-yl)morpholine

To a solution of2-(4-(3,4-dichlorobenzyl)-2-morpholinothiazol-5-yl)acetonitrile (87.0mg, 0.236 mmol) in DMF (0.74 mL) was added sodium azide (21.6 mg, 0.332mmol) and NH₄Cl (17.8 mg, 9.53 mmol) and the resulting mixture washeated to 140 degrees overnight. More sodium azide (43 mg, 0.66 mmol)and NH₄Cl (36 mg, 19 mmol) were added and the reaction was heated to 120degrees overnight. The reaction was cooled and taken up in ethyl acetate(25 mL) and water (5 ml). The layers were separated and the organiclayer was washed with water (3×5 mL).). The organic layer was dried andconcentrated in vacuo. The residue was purified by preparative reversephase chromatography to give 5 mg (5% yield) of the title compound. as awhite solid. LC/MS (FA) ES+ 411. 413. ¹H NMR (400 MHz, DMSO-d₆) δ: 7.50(d, 1H, J=8.0 Hz), 7.46 (d, 1H, J=2.0 Hz), 7.20 (dd, 1H, J=8.0, 2.0 Hz),4.41 (s, 2H), 3.88 (s, 2H), 3.65-3.62 (m, 4H), 3.32 (bs, 1H), 3.26-3.24(m, 4H).

Example 56 Synthesis of4-cyano-3-[1-(3,4-dichlorophenyl)-3-hydroxypropyl]-5-(morpholin-4-yl)thiophene-2-carboxylicacid (Compound 347)

Step 1: To a suspension of ethyl4-cyano-3-[1-(3,4-dichlorophenyl)but-3-en-1-yl]-5-(morpholin-4-yl)thiophene-2-carboxylate(247 mg, 0.531 mmol) in 1,4-dioxane (6.00 mL) and water (2.00 mL) wasadded sodium metaperiodate (454 mg, 2.12 mmol), 2,6-lutidine (246 uL,2.12 mmol), and 4% osmium tetroxide in water (4:96, osmiumtetraoxide:water, 64.9 uL, 0.0106 mmol). The reaction was vigorouslystirred at rt for 5 hrs. The mixture was filtered over a celite pad andthe filtered solid was rinsed with EtOAc. The filtrate was washed withNaHCO₃(aq) saturated solution and the aqueous layer was extracted withEtOAc (×2). The combined organic layer was washed with 1N HCl soln andbrine, dried, and concentrated. Purification on a silica gel column(gradient elution 5-50% EtOAc/hexanes) provided ethyl4-cyano-3-[1-(3,4-dichlorophenyl)-3-oxopropyl]-5-(morpholin-4-yl)thiophene-2-carboxylateas a yellow syrup (108 mg, 43.5% yield). ¹H NMR (400 MHz, CDCl₃) δ9.84-9.73 (d, J=1.3 Hz, 1H), 7.48-7.42 (d, J=2.1 Hz, 1H), 7.42-7.32 (d,J=8.4 Hz, 1H), 7.30-7.18 (m, 1H), 6.06-5.94 (t, J=7.7 Hz, 1H), 4.38-4.26(q, J=7.1 Hz, 2H), 3.86-3.77 (t, J=4.9 Hz, 4H), 3.62-3.51 (dd, J=5.7,4.0 Hz, 4H), 3.50-3.42 (m, 2H), 1.41-1.29 (m, 3H).

Step 2: To a solution of ethyl4-cyano-3-[1-(3,4-dichlorophenyl)-3-oxopropyl]-5-(morpholin-4-yl)thiophene-2-carboxylate(50.0 mg, 0.107 mmol) in ethanol (1.00 mL) was added sodiumtetrahydroborate (4.05 mg, 0.107 mmol). The mixture was stirred at rtfor 1 hr. The reaction was quenched with 1.00 M of hydrochloric acid inwater (0.428 mL) and distributed between NaHCO₃(aq) saturated solutionand EtOAc. The aqueous layer was extracted with EtOAc (×2). The combinedorganic layer was dried and concentrated to provide a white solid.Purification on a silica gel column (gradient elution 0-5% MeOH)provided ethyl4-cyano-3-[1-(3,4-dichlorophenyl)-3-hydroxypropyl]-5-(morpholin-4-yl)thiophene-2-carboxylateas a colorless syrup (38 mg, 75.7% yield). ¹H NMR (400 MHz, CDCl₃) δ7.46-7.35 (dd, J=5.2, 3.1 Hz, 2H), 7.30-7.19 (m, 1H), 5.65-5.52 (t,J=8.0 Hz, 1H), 4.42-4.26 (q, J=7.1 Hz, 2H), 3.85-3.77 (t, J=4.9 Hz, 4H),3.76-3.65 (ddt, J=13.0, 9.0, 4.6 Hz, 1H), 3.57-3.44 (t, J=4.8 Hz, 5H),2.69-2.58 (dd, J=8.4, 4.1 Hz, 1H), 2.56-2.43 (dt, J=8.1, 4.9 Hz, 2H),1.44-1.32 (t, J=7.1 Hz, 3H).

Step 3: To a solution of ethyl4-cyano-3-[1-(3,4-dichlorophenyl)-3-hydroxypropyl]-5-(morpholin-4-yl)thiophene-2-carboxylate(38.0 mg, 0.0810 mmol) in tetrahydrofuran (1.00 mL) was added NaH 60% inmineral oil (60:40, Sodium hydride:mineral Oil, 3.56 mg, 0.0890 mmol).The mixture was heated to 60° C. for 3 hrs. The reaction was cooled tort and distributed between brine and EtOAc. The aqueous layer wasextracted with EtOAc (×2). The combined organic layer was washed withbrine, dried, and concentrated to provide a yellow solid. Purificationon HPLC (reverse phase, AA) provided4-cyano-3-[1-(3,4-dichlorophenyl)-3-hydroxypropyl]-5-(morpholin-4-yl)thiophene-2-carboxylicacid as a white solid (6.5 mg, 18.2% yield). LCMS: (AA) ES+ 441, 443,445; ¹H NMR (400 MHz, MeOD) δ 7.50-7.45 (s, 1H), 7.45-7.37 (d, J=8.4 Hz,1H), 7.30-7.22 (m, 1H), 5.79-5.63 (m, 1H), 3.83-3.71 (t, J=4.8 Hz, 4H),3.60-3.50 (q, J=6.9, 6.0 Hz, 2H), 3.50-3.41 (d, J=3.2 Hz, 4H), 2.52-2.37(m, 2H).

Example 57 Synthesis of4-cyano-3-[1-(3,4-dichlorophenyl)-3-(dimethylamino)propyl]-5-(morpholin-4-yl)thiophene-2-carboxylicacid (Compound 331)

Step 1: To a solution of ethyl4-cyano-3-[1-(3,4-dichlorophenyl)-3-oxopropyl]-5-(morpholin-4-yl)thiophene-2-carboxylate(38.0 mg, 0.0813 mmol) (from example 56, step 1) in methanol (1.00 mL)was added dimethylamine hydrochloride (9.94 mg, 0.122 mmol), sodiumacetate (8.00 mg, 0.0976 mmol), and sodium cyanoborohydride (6.13 mg,0.0976 mmol). The reaction was stirred at rt for 2 h. The mixture wasdistributed between NaHCO₃(aq) saturated solution and EtOAc. The aqueouslayer was extracted with EtOAc (×2). The combined organic layer wasdried and concentrated. Purification on a silica gel column (gradientelution, 0-15% MeOH/CH₂Cl₂) provided ethyl4-cyano-3-[1-(3,4-dichlorophenyl)-3-(dimethylamino)propyl]-5-(morpholin-4-yl)thiophene-2-carboxylateas a yellow syrup (29.0 mg, 71.8% yield). LCMS: (AA) ES+ 496, 498, 500;¹H NMR (400 MHz, CDCl₃) δ 7.52-7.44 (d, J=1.9 Hz, 1H), 7.41-7.34 (m,1H), 7.33-7.27 (m, 1H), 5.54-5.40 (t, J=7.7 Hz, 1H), 4.38-4.27 (q, J=7.1Hz, 2H), 3.88-3.76 (t, J=4.9 Hz, 4H), 3.58-3.49 (dd, J=5.7, 4.0 Hz, 4H),2.57-2.31 (m, 3H), 2.29-2.24 (s, 6H), 2.24-2.16 (m, 1H), 1.41-1.30 (t,J=7.1 Hz, 3H).

Step 2: To a solution of ethyl4-cyano-3-[1-(3,4-dichlorophenyl)-3-(dimethylamino)propyl]-5-(morpholin-4-yl)thiophene-2-carboxylate(29.0 mg, 0.0584 mmol) in methanol (0.500 mL) was added 1.030 M ofsodium hydroxide in water (284 uL, 0.284 mmol). The reaction was stirredat rt over 2 days. The mixture was neutralized with 1.00 M ofhydrochloric acid in water (0.292 mL), diluted with 5 mL of water andextracted with 10% MeOH/CHCl₃ (×5). The combined organic layer was driedand concentrated, and the resulting white syrup/solid was lyophilized toprovide4-cyano-3-[1-(3,4-dichlorophenyl)-3-(dimethylamino)propyl]-5-(morpholin-4-yl)thiophene-2-carboxylicacid as a white solid (26 mg, 95% yield). LCMS: (AA) ES+ 468, 470, 472;¹H NMR (400 MHz, DMSO) δ 7.63-7.52 (d, J=8.4 Hz, 1H), 7.44-7.37 (s, 1H),7.15-7.02 (d, J=8.1 Hz, 1H), 5.49-5.34 (d, J=9.4 Hz, 1H), 3.73-3.63 (t,J=4.8 Hz, 4H), 3.38-3.31 (dd, J=6.2, 4.0 Hz, 4H), 3.13-2.97 (s, 1H),2.85-2.73 (s, 1H), 2.72-2.60 (s, 6H), 2.56-2.52 (m, 1H).

Example 58 Synthesis of3-(3,4-dichlorobenzyl)-4-fluoro-5-morpholinothiophene-2-carboxylic acid(Compound 320)

Step 1, Preparation of4-bromo-3-(3,4-dichlorobenzyl)-5-morpholinothiophene-2-carboxylic acid

To a solution of ethyl4-bromo-3-(3,4-dichlorobenzyl)-5-morpholinothiophene-2-carboxylate (109mg, 0.227 mmol) in THF (1.8 mL) and MeOH (0.37 mL) was added 1.00 Maqueous NaOH (1.82 mL, 1.82 mmol) and the resulting mixture was stirredat 45° C. overnight. The reaction was diluted with water (5 mL) andacidified to pH=3 with 1 N HCl. The mixture was extracted with ethylacetate (2×20 mL) and the combined organic layers were dried, filteredand concentrated in vacuo to give 92 mg (90% yield) of a white solidwhich was used as is in the next step. LC/MS (AA) ES+ 450, 452, 454. ¹HNMR (400 MHz, DMSO-d₆) δ: 13.21 (bs, 1H), 7.52 (d, 1H, J=8.0 Hz), 7.39(d, 1H, 2.0 Hz), 7.09 (dd, 1H, J=8.0, 2.0 Hz), 4.36 (s, 2H), 3.74-3.71(m, 4H), 3.13-3.11 (m, 4H).

Step 2, Preparation of3-(3,4-dichlorobenzyl)-4-fluoro-5-morpholinothiophene-2-carboxylic acid

To a solution of4-bromo-3-(3,4-dichlorobenzyl)-5-morpholinothiophene-2-carboxylic acid(89.0 mg, 0.197 mmol) in THF (3.00 mL) in a dry-ice/acetone bath wasadded 1.60 M BuLi in hexanes (0.271 mL, 0.434 mmol) and the resultingsolution was stirred for 10 minutes at −78° C. A solution ofN-fluoro-N-(phenylsulfonyl)benzenesulfonamide (93.3 mg, 0.296 mmol) inTHF (0.70 mL) was then added and the reaction was allowed to warm to 0°C. The reaction was quenched with saturated NH₄Cl (5 mL) and ethylacetate (15 mL) was then added. The layers were separated and theaqueous layer was acidified to pH=3 with 1N HCl. The acidic aqueouslayer was extracted with ethyl acetate (2×20 mL) and the combinedorganic layers were dried, filtered and concentrated in vacuo. Theresidue was purified by silica gel chromatography (MeOH/DCM=0/100→15/85)to give 31 mg of product. This material was purified by preparativereverse phase chromatography to give 9 mg (10% yield) of the titlecompound. as a white solid. LC/MS (FA) ES+ 390, 392. ¹H NMR (400 MHz,DMSO-d₆) δ: 13.04 (bs, 1H), 7.54 (d, 1H, J=8.0 Hz), 7.44 (d, 1H, J=1.6Hz), 7.16 (dd, 1H, J=8.0, 1.6 Hz), 4.21 (s, 2H), 3.71-3.68 (m, 4H),3.14-3.12 (m, 4H).

Example 59 Synthesis of4-cyano-5-(morpholin-4-yl)-3-[(4-oxoquinazolin-3(4H)-yl)methyl]thiophene-2-carboxylicacid (Compound 294)

Step 1: Methyl4-cyano-5-(morpholin-4-yl)-3-[(4-oxoquinazolin-3(4H)-yl)methyl]thiophene-2-carboxylate

Under N₂ atmosphere Sodium hydride (23.0 mg, 0.910 mmol) was suspendedin anhydrous N,N-Dimethylformamide (3.0 mL, 39 mmol), cooled with icebath and stirred for 10 min. 4-hydroxyquinazoline (0.120 g, 0.821 mmol)was added and the clear solution was stirred at r.t. for 10 min, cooledwith ice bath. Methyl3-(bromomethyl)-4-cyano-5-(morpholin-4-yl)thiophene-2-carboxylate (0.203g, 0.588 mmol) was added and the reddish-brown solution was stirred withcooling for 40 min. The mixture was quenched with saturated NH4Claqueous solution, extracted with EtOAc. The EtOAc solution was washedwith water (3×) then brine, dried over Na₂SO₄, filtered, rotavaped togive a crude solid. Chromatograph in a silica gel column using MeOH/DCM(0/100 to 5/95) afforded a solid product (0.211 g, yield 87.4%). LC/MS:(FA) ES⁺ 411. ¹H NMR (400 MHz, d-chloroform) δ 8.30 (m, 1H), 8.26 (s,1H), 7.68-7.76 (m, 2H), 7.45-7.49 (m, 1H), 5.43 (s, 2H), 3.83-3.85 (m,4H), 3.82 (s, 3H), 3.59-3.62 (m, 4H).

Step 2:4-Cyano-5-(morpholin-4-yl)-3-[(4-oxoquinazolin-3(4H)-yl)methyl]thiophene-2-carboxylicacid sodium salt

Methyl4-cyano-5-(morpholin-4-yl)-3-[(4-oxoquinazolin-3(4H)-yl)methyl]thiophene-2-carboxylate(0.139 g, 0.339 mmol) was dissolved in Tetrahydrofuran (15.0 mL), Water(2.0 mL) and Methanol (5.0 mL). 1.00 M of Sodium hydroxide in Water (1.0mL, 1.0 mmol) was added and the homogeneous solution was stirred at roomtemperature for 24 hours. The solution was concentrated in rotavapor togive a white crude solid, dissolved in H2O/MeOH (1/10, ˜20 mL) andconcentrated in rotavapor until a white suspension (˜2 mL volume). Thesuspension was filtered to collect the solid, dried in lypholizer togive a white solid product (0.132 g, yield 92.2%). LC/MS: (FA) ES⁺ 397;ES⁻ 395. ¹H NMR (400 MHz, d4-methanol) δ 8.37 (s, 1H), 8.22 (d, J=8.03Hz, 1H), 7.78-7.82 (m, 1H), 7.65 (d, J=7.28 Hz, 1H), 7.51-7.55 (m, 1H),5.99 (s, 2H), 3.78-3.81 (m, 4H), 3.47-3.50 (m, 4H).

Example 60 Synthesis of4-(3,4-dichlorobenzyl)-N-hydroxy-2-(morpholin-4-yl)-1,3-thiazole-5-carboxamide(Compound 298)

Step 1: To a suspension of4-(3,4-dichlorobenzyl)-2-morpholin-4-yl-1,3-thiazole-5-carboxylicacid.Na (125 mg, 0.316 mmol),N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (72.8 mg,0.380 mmol), and 1-hydroxybenzotriazole (51.3 mg, 0.380 mmol) inN,N-dimethylformamide (1.50 mL) was addedO-(tetrahydropyran-2-yl)hydroxylamine (55.6 mg, 0.474 mmol). Thereaction was stirred at rt for 15 hrs. The mixture was distributedbetween water and EtOAc, and the aqueous layer was extracted with EtOAc(×2). The combined organic layer was washed with NaHCO₃(aq) saturatedsolution and 10% LiCl(aq) soln (×2), dried over Na₂SO₄, and concentratedto provide4-(3,4-dichlorobenzyl)-2-(morpholin-4-yl)-N-(tetrahydro-2H-pyran-2-yloxy)-1,3-thiazole-5-carboxamideas a white solid (153 mg, quantitative). LCMS: (AA) ES+ 472, 474, 476;¹H NMR (400 MHz, CDCl₃) δ 7.49-7.43 (d, J=1.9 Hz, 1H), 7.30-7.26 (m,1H), 7.26-7.17 (m, 1H), 5.01-4.89 (d, J=2.8 Hz, 1H), 4.31-4.21 (m, 2H),3.96-3.86 (td, J=10.4, 9.1, 2.8 Hz, 1H), 3.80-3.70 (t, J=4.9 Hz, 4H),3.66-3.56 (m, 1H), 3.51-3.42 (t, J=4.9 Hz, 4H), 1.90-1.73 (m, 3H),1.69-1.49 (m, 3H).

Step 2: To a solution of4-(3,4-dichlorobenzyl)-2-(morpholin-4-yl)-N-(tetrahydro-2H-pyran-2-yloxy)-1,3-thiazole-5-carboxamide(153 mg, 0.324 mmol) in methylene chloride (1.50 mL) was addedtrifluoroacetic Acid (1.50 mL, 19.5 mmol). The reaction was stirred atrt for 12 hrs. The resulting solution was concentrated and distributedbetween NaHCO₃(aq) saturated solution and CH₂Cl₂. The aqueous layer wasextracted with CH₂Cl₂ (×2). The combined org layer was washed withwater, dried, and concentrated. Purification on a silica gel column(gradient elution, 0-8% MeOH/CH₂Cl₂) provided4-(3,4-dichlorobenzyl)-N-hydroxy-2-(morpholin-4-yl)-1,3-thiazole-5-carboxamideas a yellow solid (53 mg, 42.1% yield). LCMS: (AA) ES+ 388, 390, 392; ¹HNMR (400 MHz, MeOD) δ 7.47-7.41 (d, J=1.8 Hz, 1H), 7.38-7.29 (d, J=8.3Hz, 1H), 7.25-7.14 (dd, J=8.3, 1.9 Hz, 1H), 4.28-4.21 (s, 2H), 3.79-3.71(t, J=4.9 Hz, 4H), 3.50-3.43 (t, J=4.9 Hz, 4H), 3.33-3.27 (t, J=1.6 Hz,1H).

Compounds in the following table are prepared from appropriate startingmaterials in a method analogous to that of Example 60.

334 LC/MS: (AA) ES+ 354

Example 61 Synthesis of2-(morpholin-4-yl)-4-(2-naphthylmethyl)-5-(1H-tetrazol-5-yl)thiophene-3-carbonitrile(Compound 316)

Step 1: To a mixture of4-cyano-5-morpholin-4-yl-3-(2-naphthylmethyl)thiophene-2-carboxylicacid.Na (255 mg, 0.637 mmol) in N,N-dimethylformamide (6.00 mL) wasadded 1-hydroxybenzotriazole hydrate (117 mg, 0.764 mmol),N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (146 mg,0.764 mmol), and 0.500 M of ammonia in 1,4-dioxane (3.18 mL, 1.59 mmol).The reaction was vigorously stirred at rt for 5 hrs. The mixture wasdistributed between brine and EtOAc, and the aqueous layer was extractedwith EtOAc (×2). The combined organic layers were washed with 10%LiCl(aq) solution (×2), dried, and concentrated to provide4-cyano-5-(morpholin-4-yl)-3-(2-naphthylmethyl)thiophene-2-carboxamide(Compound 327) as a white solid (224 mg, 93.2% yield). LCMS: (AA) ES+378; ¹H NMR (400 MHz, DMSO) δ 7.89-7.76 (td, J=11.0, 6.6 Hz, 3H),7.68-7.62 (s, 1H), 7.51-7.44 (td, J=6.8, 6.0, 3.7 Hz, 3H), 7.43-7.34 (m,1H), 4.50-4.42 (s, 2H), 3.78-3.69 (t, J=4.9 Hz, 4H), 3.50-3.40 (t, J=4.9Hz, 4H).

Step 2: To a mixture of sodium azide (153 mg, 2.35 mmol) in acetonitrile(2.50 mL) in a 20 mL microwave tube was added silicon(IV) chloride (89.9uL, 0.783 mmol). The mixture was stirred at rt under an atmosphere ofNitrogen for 20 min, then4-cyano-5-(morpholin-4-yl)-3-(2-naphthylmethyl)thiophene-2-carboxamide(197 mg, 0.522 mmol) was added. The tube was sealed and the reaction washeated to 90° C. for 12 hrs. The mixture was cooled and distributedbetween water and EtOAc. The aqueous layer was extracted with EtOAc(×2). The combined organic layer was washed with brine, dried, andconcentrated to provide a purple syrup. Purification on HPLC (reversephase, AA) provided2-(morpholin-4-yl)-4-(2-naphthylmethyl)-5-(1H-tetrazol-5-yl)thiophene-3-carbonitrileas a yellow solid (44 mg, 20.9% yield). LCMS: (AA) ES+ 403; ¹H NMR (400MHz, MeOD) δ 7.78-7.73 (m, 1H), 7.73-7.67 (d, J=7.8 Hz, 2H), 7.67-7.61(s, 1H), 7.42-7.36 (m, 2H), 7.36-7.30 (m, 1H), 4.63-4.57 (s, 2H),3.85-3.76 (t, J=4.9 Hz, 4H), 3.57-3.48 (t, J=4.8 Hz, 4H).

Example 62 Synthesis of4-[4-(2-naphthylmethyl)-5-(1H-tetrazol-5-yl)-1,3-thiazol-2-yl]morpholine(Compound 360)

Step 1: A mixture of2-(morpholin-4-yl)-4-(2-naphthylmethyl)-1,3-thiazole-5-carboxamide (229mg, 0.648 mmol) (for amide coupling, see example 61-step 1) andphosphoryl chloride (4.00 mL, 42.9 mmol) was stirred at 80° C. for 30min. The reaction slowly turned homogeneous. The resulting solution wasconcentrated under reduced pressure and carefully quenched with 1N NaOHsolution at 0° C. The resulting mixture was distributed between 1N NaOHsolution and EtOAc. The aqueous layer was extracted with EtOAc. Thecombined organic layer was dried and concentrated to provide2-(morpholin-4-yl)-4-(2-naphthylmethyl)-1,3-thiazole-5-carbonitrile as ayellow solid (213 mg, 98.0% yield). LCMS: (AA) ES+ 336; ¹H NMR (400 MHz,DMSO) δ 7.90-7.83 (dd, J=9.0, 1.9 Hz, 3H), 7.80-7.72 (s, 1H), 7.53-7.46(m, 2H), 7.46-7.38 (m, 1H), 4.18-4.09 (s, 2H), 3.70-3.60 (t, J=4.9 Hz,4H), 3.51-3.41 (t, J=4.9 Hz, 4H).

Step 2: To a solution of2-(morpholin-4-yl)-4-(2-naphthylmethyl)-1,3-thiazole-5-carbonitrile (213mg, 0.635 mmol) in N,N-dimethylformamide (3.00 mL) was added sodiumazide (61.9 mg, 0.952 mmol) and ammonium chloride (102 mg, 1.90 mmol).The mixture was heated to 100° C. and stirred for 24 hrs. The resultingmixture was cooled to rt and distributed between water and EtOAc. Theaqueous layer was extracted with EtOAc (×2). The combined organic layerwas washed with 10% LiCl(aq) solution (×2), dried, and concentrated.Purification on HPLC (reverse phase, AA) provided4-[4-(2-naphthylmethyl)-5-(1H-tetrazol-5-yl)-1,3-thiazol-2-yl]morpholineas a yellow solid (105 mg, 43.7% yield). LCMS: (AA) ES+ 379; ¹H NMR (400MHz, MeOD) δ 7.79-7.61 (m, 4H), 7.43-7.31 (m, 3H), 4.57-4.45 (s, 2H),3.82-3.68 (t, J=4.9 Hz, 4H), 3.53-3.43 (t, J=4.9 Hz, 4H).

Compounds in the following table are prepared from appropriate startingmaterials in a method analogous to that of Example 62.

356 LC/MS: (AA) ES+ 378

Example 63 Synthesis of4-cyano-3-(3,4-dichlorobenzyl)-N-(methylsulfonyl)-5-morpholinothiophene-2-carboxamide(Compound 352)

To a mixture of4-cyano-3-(3,4-dichlorobenzyl)-5-morpholinothiophene-2-carboxylic acid(291 mg, 0.732 mmol), in DCM (5.0 mL) was added methanesulfonamide (87.1mg, 0.916 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimidehydrochloride (176 mg, 0.916 mmol), and N,N-dimethylaminopyridine (103mg, 0.842 mmol) and the resulting solution was stirred at roomtemperature overnight. The reaction was diluted with DCM (10 mL), 1N HCl(3 mL) and with water (3 mL). The organic layer was dried, filtered andconcentrated in vacuo. The residue was purified by silica gelchromatography (MeOH/DCM=0/100→20/80) to give 250 mg of crude product.This material was purified by preparative reverse phase chromatographyto give 70 mg (20% yield) of the title compound. as a white solid. LC/MS(FA) ES+ 474, 476. ¹H NMR (400 MHz, MeOH-d₄) δ: 7.45 (d, 1H, J=2.0 Hz)),7.38 (d, 1H, J=8.4 Hz), 7.25 (dd, 1H, J=8.0, 2.0 Hz), 4.38 (s, 2H),3.82-3.80 (m, 4H), 3.57-3.55 (m, 4H), 3.18 (s, 3H).

Example 64 Synthesis of3-(3,4-dichlorobenzyl)-5-(morpholin-4-yl)-4-(phenylethynyl)thiophene-2-carboxylicacid (Compound 296)

Step 1: Ethyl 3,4-dibromo-5-(morpholin-4-yl)thiophene-2-carboxylate

To a degassed solution of ethyl3-bromo-5-morpholin-4-ylthiophene-2-carboxylate (0.688 g, 2.15 mmol) inDMF (14 mL, 180 mmol) was added N-bromosuccinimide (0.7648 g, 4.297mmol) dropwise as a solution in degassed DMF (4.1 mL, 52 mmol). Themixture was wrapped in foil to protect from ambient light, and thereaction was stirred under argon at room temperature for 2 hours. Thereaction mixture was quenched via addition of 10% sodium thiosulfatesolution (10 mL) and then diluted with EtOAc (30 mL). The layers wereseparated, and the aqueous layer was extracted with EtOAc (10 mL). Thecombined organic layers were washed with brine, dried over Na₂SO₄,filtered, and concentrated in vacuo. Flash chromatography (eluent: 0-25%EtOAc:hexane) afforded ethyl3,4-dibromo-5-(morpholin-4-yl)thiophene-2-carboxylate (593 mg, yield69%). LCMS: (FA) ES+ 398, 400, 402; ¹H NMR (400 MHz, DMSO) δ 4.26 (q,J=7.1 Hz, 2H), 3.75 (dd, J=5.5, 3.8 Hz, 4H), 3.24-3.10 (m, 4H), 1.27 (t,J=7.1 Hz, 3H).

Step 2: Ethyl4-bromo-3-(3,4-dichlorobenzyl)-5-(morpholin-4-yl)thiophene-2-carboxylate

A sealable reaction vessel containing a suspension of ethyl3,4-dibromo-5-(morpholin-4-yl)thiophene-2-carboxylate (0.560 g, 1.40mmol), 0.500 M 3,4-dichlorobenzylzinc chloride in THF (3.368 mL, 1.684mmol) and THF (2.06 mL, 25.4 mmol) was purged via vacuum/backfillingwith argon. To this suspension was addedtetrakis(triphenylphosphine)palladium(0) (81.07 mg, 0.07016 mmol), thevial was capped, and the resulting black suspension was stirred at 95°C. overnight. The reaction mixture was adsorbed to celite in vacuo, andthe solid thus obtained was purified via column chromatography (eluent:0-15% EtOAc:hexane) to afford ethyl4-bromo-3-(3,4-dichlorobenzyl)-5-(morpholin-4-yl)thiophene-2-carboxylate(323 mg, 50%). LCMS: (FA) ES+ 478, 480, 482; ¹H NMR (400 MHz, DMSO) δ7.53 (d, J=8.3 Hz, 1H), 7.39 (d, J=2.0 Hz, 1H), 7.07 (dd, J=8.3, 2.1 Hz,1H), 4.36 (s, 2H), 4.22 (q, J=7.1 Hz, 2H), 3.75-3.70 (m, 4H), 3.17-3.12(m, 4H), 1.22 (t, J=7.1 Hz, 3H).

Step 3: Ethyl3-(3,4-dichlorobenzyl)-5-(morpholin-4-yl)-4-(phenylethynyl)-thiophene-2-carboxylate

To a suspension of ethyl4-bromo-3-(3,4-dichlorobenzyl)-5-(morpholin-4-yl)thiophene-2-carboxylate(0.125 g, 0.000222 mol), XPhos (0.0172 g, 0.0000362 mol), CsCO₃ (0.199g, 0.000612 mol) and phenylacetylene (0.146 mL, 0.00133 mol) in DMF (1.2mL, 0.015 mol) was added bis(acetonitrile)palladium(II) chloride(0.00288 g, 0.0000111 mol) and the mixture was heated at 50° C.overnight. The reaction mixture was diluted with EtOAc (30 mL) and water(15 mL), and the layers were separated. The aqueous layer was extractedwith EtOAc (2×15 mL). Combined organic layers were dried over Na₂SO₄,filtered, and concentrated. The crude residue was purified using a dryload on a silica gel column (eluent: 0-30% EtOAc:hexane), affordingethyl3-(3,4-dichlorobenzyl)-5-(morpholin-4-yl)-4-(phenylethynyl)thiophene-2-carboxylate(45 mg, 40% yield). LC/MS: (FA) ES+ 500, 501, 502; ¹H NMR (400 MHz,DMSO) δ 7.55-7.51 (m, 2H), 7.43-7.37 (m, 5H), 7.20 (dd, J=8.3, 2.0 Hz,1H), 4.38 (s, 2H), 4.22 (q, J=7.1 Hz, 2H), 3.79-3.74 (m, 4H), 3.57-3.52(m, 4H), 1.23 (t, J=7.1 Hz, 3H).

Step 4:3-(3,4-dichlorobenzyl)-5-(morpholin-4-yl)-4-(phenylethynyl)-thiophene-2-carboxylicacid

To a suspension of ethyl3-(3,4-dichlorobenzyl)-5-(morpholin-4-yl)-4-(phenylethynyl)thiophene-2-carboxylate(0.041 g, 0.082 mmol in THF (2.00 mL, 24.6 mmol) and methanol (0.37 mL,9.1 mmol) was added 1.000 M of sodium hydroxide in water (1.684 mL,1.684 mmol) and the resulting biphasic mixture was stirred at room tempfor 2 days. The pH was carefully adjusted to 3.0 via addition of 1N HCl(monitored in real time with a pH meter), and the reaction mixture wastransferred to a reparatory funnel. The mixture was diluted with EtOAc(40 mL) and water (15 mL), and the layers were separated. The aqueouslayer was extracted with EtOAc (2×30 mL). The combined organic layerswere washed with brine, then dried over Na₂SO₄, filtered, andconcentrated. Column chromatography (eluent: 0-5% MeOH:DCM) afforded3-(3,4-dichlorobenzyl)-5-(morpholin-4-yl)-4-(phenylethynyl)thiophene-2-carboxylicacid (30 mg, 78% yield). LCMS: (FA) ES+ 472, 473, 474; ¹H NMR (400 MHz,DMSO) δ 12.92 (s, 1H), 7.55-7.50 (m, 2H), 7.43-7.34 (m, 5H), 7.21 (dd,J=8.3, 2.0 Hz, 1H), 4.39 (s, 2H), 3.81-3.68 (m, 4H), 3.56-3.42 (m, 4H).

Example 65 Synthesis of2-(4-(3,4-dichlorobenzyl)-2-morpholinothiazol-5-yl)acetic acid (Compound348)

To a solution of2-(4-(3,4-dichlorobenzyl)-2-morpholinothiazol-5-yl)acetonitrile (165 mg,0.448 mmol) in IPA (4.88 mL) was added 50% aqueous NaOH (1.68 mL, 44.8mmol) and the resulting solution was heated to 90 degrees for 3 hours.The reaction was cooled and concentrated in vacuo. The residue wasacidified with 1 N HCl and extracted with ethyl acetate (2×25 mL). Thecombined organic layers were dried, filtered and concentrated in vacuo.The residue was purified by silica gel chromatography(MeOH/DCM=0/100→20/80) to give 120 mg of product. This material waspurified by preparative reverse phase chromatography to give 16 mg (9%yield) of the title compound. as a white solid. LC/MS (FA) ES+ 387, 389.¹H NMR (400 MHz, DMSO-d₆) δ: 7.49 (d, 1H, J=8.0 Hz), 7.47 (d, 1H, J=2.0Hz), 7.21 (dd, 1H, J=8.0, 2.0 Hz), 3.78 (s, 2H), 3.67 (s, 2H), 3.66-3.63(m, 4H), 3.26-3.24 (m, 4H).

Example 66 Synthesis of4-(4-chlorobenzyl)-2-morpholino-1,3-selenazole-5-carboxylic acid(Compound 370)

Step 1: Morpholine-4-carboselenoamide

In a round bottomed flask equipped with a stir bar were added seleniummetal (4.00 g, 49.4 mmol) and ethanol (50 mL). The mixture was cooled inan ice bath and stirred under a nitrogen atmosphere while sodiumtetrahydroborate (2.01 g, 53.1 mmol) was slowly added. Gas was evolvedand the selenium slowly dissolved. After gas evolution had ceased,4-morpholinecarbonitrile (2.77 g, 24.7 mmol) was slowly added followedby pyridine hydrochloride (11.4 g, 98.7 mmol). The resulting darkmixture was stirred overnight at room temperature. The grayish reactionmixture was quenched with water (−250 mL) and the mixture was stirredbriefly then transferred to a reparatory funnel. The mixture wasextracted with dichloromethane (3×). The extracts were combined anddried over sodium sulfate. The insolubles were filtered off and thefiltrate was evaporated to leave a light pink solid which was stirredwith water then filtered. The collected solid was washed with ethylacetate and the washings were combined then evaporated to leave 80 mg(2% yield) product as a light pink solid. LC/MS (FA) ES+ 195. ¹H NMR(400 MHz, DMSO) δ 8.15-7.71 (br s, 2H), 3.94-3.61 (br s, 4H), 3.60-3.51(t, J=4.9 Hz, 4H).

Step 2: Ethyl4-(4-chlorobenzyl)-2-morpholino-1,3-selenazole-5-carboxylate

In a round bottomed flask were placed ethyl2-chloro-4-(4-chlorophenyl)-3-oxobutanoate (84.4 mg, 0.3069 mmol),isopropyl alcohol (5 mL), and morpholine-4-carboselenoamide (80.0 mg,0.414 mmol). The resulting mixture was brought to reflux under anatmosphere of nitrogen (all solids dissolved to give a clear pale pinksolution). After ˜1 hour reflux, TLC analysis indicated that allstarting materials had been consumed with the production of one majorproduct. The reaction was allowed to cool to room temperature and stirovernight. The solvent was removed on the rotovap then the residue wasdissolved in minimal dichloromethane and purified by columnchromatography on silica gel (gradient 100% hexane to 35% ethyl acetate)to afford 35 mg (28% yield) product as a white solid. LC/MS (FA) ES+413/415/417. ¹H NMR (400 MHz, DMSO) δ 7.37-7.23 (m, 4H), 4.25-4.14 (m,4H), 3.72-3.62 (t, J=4.9 Hz, 4H), 3.50-3.41 (t, J=4.8 Hz, 4H), 1.27-1.20(t, J=7.1 Hz, 3H).

Step 3: 4-(4-chlorobenzyl)-2-morpholino-1,3-selenazole-5-carboxylic acid

The ethyl4-(4-chlorobenzyl)-2-(morpholin-4-yl)-1,3-selenazole-5-carboxylate (35.0mg, 0.0846 mmol) was placed in a round bottomed flask equipped with astirbar. Tetrahydrofuran (1.00 mL) and methanol (0.1 mL) were added andthe mixture was stirred to give a light yellow solution. A solution oflithium hydroxide in water (2.0 M, 0.423 mL, 0.846 mmol) was added in asingle portion, and the resulting mixture was stirred under anatmosphere of nitrogen at room temperature overnight. LCMS analysis ofthe reaction indicated that starting material still remained; only asmall amount of it had been hydrolyzed to the product. Additionaltetrahydrofuran (2 mL) and lithium hydroxide in water (2.0 M, 0.423 mL,0.846 mmol) were added and the reaction was heated overnight at 50° C.under an atmosphere of nitrogen. LCMS analysis indicated that thereaction was 90% complete. The reaction was heated at 60° C. for afurther 8 hours. LCMS analysis indicated complete hydrolysis. Thereaction was cooled to room temperature, diluted with 10 ml saline, andacidified with dilute acetic acid with good stirring. A whiteprecipitate formed which became granular with stirring. The product wasisolated on a fritted funnel, washed with water, and dried at 40° C.overnight to yield 29.2 mg (89% yield) product as a white powder. LC/MS(FA) ES+ 385/387/389. ¹H NMR (400 MHz, DMSO) δ 12.73-12.44 (br s, 1H),7.36-7.24 (m, 4H), 4.26-4.18 (s, 2H), 3.74-3.63 (t, J=4.8 Hz, 4H),3.49-3.39 (t, J=4.7 Hz, 4H).

Formulation Example 1 Amount Per Tablet

(1) Compound obtained in Example 1 10.0 mg (2) Lactose 60.0 mg (3) Cornstarch 35.0 mg (4) Gelatin  3.0 mg (5) Magnesium stearate  2.0 mg

A mixture of 10.0 mg of the compound obtained in Example 1, 60.0 mg oflactose and 35.0 mg of corn starch is granulated through a 1 mm-meshsieve using 0.03 ml of a 10% by weight aqueous solution of gelatin (3.0mg of gelatin), after which the granules are dried at 40° C. andfiltered again. The granules obtained are mixed with 2.0 mg of magnesiumstearate and compressed. The core tablets obtained are coated with asugar coat comprising a suspension of sucrose, titanium dioxide, talcand gum arabic and polished with beeswax to yield sugar-coated tablets.

Formulation Example 2 Dose Per Tablet

(1) Compound obtained in Example 1 10.0 mg (2) Lactose 70.0 mg (3) Cornstarch 50.0 mg (4) Soluble starch  7.0 mg (5) Magnesium stearate  3.0 mg

10.0 mg of the compound obtained in Example 1 and 3.0 mg of magnesiumstearate are granulated using 0.07 ml of an aqueous solution of solublestarch (7.0 mg of soluble starch), after which these granules are driedand mixed with 70.0 mg of lactose and 50.0 mg of corn starch. Thismixture is compressed to yield tablets.

Biological Data:

PI3K and VPS34 Enzyme Assays

Cloning, Expression, and Purification of PI3Ks and VPS34

The catalytic subunits of PI3Ks are cloned into either pDEST8(p110alpha) or pDEST10(p110beta, p110delta, and p110gamma) as N-terminal Histagged fusion proteins using the Gateway system (Invitrogen, catalog#11804-010 for pDEST8 and 11806-015 for pDEST10). The sequences areverified before recombinant protein expression using the BaculovirusExpression System with Gateway® Technology. The accession numbers forthe subunits are as follows:

p110 alpha (GB:U79143)

p110beta (GB:S67334)

p1010delta (GB: U86453)

p110gamma (GB: X83368)

The regulatory subunits of PI3Ks are cloned into pDEST8 as un-taggedprotein using the Gateway system (Catalog #11804-010). The sequences areverified before recombinant protein expression using the BaculovirusExpression System with Gateway® Technology. The accession numbers forthe subunits are as following:

p85 alpha (GB: BCO030815)

p101(GB: AB028925)

VPS34 (accession number GB:BC033004) is cloned into pDEST20-Thombin asN-terminal GST tagged fusion proteins using the Gateway system(Invitrogen, catalog #11804-013). The sequences are verified beforerecombinant protein expression using the Baculovirus Expression Systemwith Gateway® Technology.

For expression of the p110 complexes, the p85 (MOI of 4) is co-infectedwith p110 alpha, beta, and delta respectively (1 MOI) in SF9 cells andharvested at 60 hours post co-infection. P110 gamma was infected at 1MOI and harvested at 60 hours post infection.

For purification, PI3Ks are purified by Ni-NTA Agarose (Qiagen #30250)followed by Mono Q 10/100 GL (Ge Healthcare #17-5167-01). VPS34 ispurified by Glutathione Sepharose 4 Fast Flow (GE Healthcare#17-5132-03) followed by HiTrap Q (GE Healthcare #17-1153-01).

For expression VPS34 was infected at 1 MOI in SF9 cells and harvested 72hours post infection.

For purification, VPS34 is purified by Glutathione Sepharose 4 Fast Flow(GE Healthcare #17-5132-03) followed by HiTrap Q (GE Healthcare#17-1153-01).

PI3K and VPS34 Assay Conditions

1) Human PI3K alpha enzyme assay method

0.5 uL compounds in DMSO are added to wells of a 384 well microtitreplate (Corning 3575). At room temperature: 10 ul PI3K reaction buffer(50 mM Hepes, 5 mM DTT, 150 mM NaCl, 10 mM beta-glycerophosphate, 10 mMMgCl2, 0.25 mM sodium cholate and 0.001% CHAPS, pH 7.00) containing ATP(25 uM, Promega) is added followed immediately by 10 ul PI3K reactionbuffer containing di-C8 PI(4,5)P2 (3.5 uM, CellSignals) and PI3Kalpha(0.4875 nM, Millennium Protein Sciences Group) and the mixture isincubated with shaking at room temperature for 30 minutes. Then 5 ulPI3K stop mix (50 mM Hepes, 5 mM DTT, 150 mM NaCl, 0.01% Tween-20, 15 mMEDTA and 25 uM biotin-PI(3,4,5)P3 (Echelon) is added to quench thereaction followed immediately by addition of 5 ul HTRF detection mix (50mM Hepes, 5 mM DTT, 150 mM NaCl, 0.01% Tween-20, 40 mM KF, 10 nMGST:GRP-1 PH domain (Millennium Protein Sciences Group), 15 nMStreptavidin-XL (CisBio) and 0.375 nM anti-GST Eu++ antibody (CisBio) atpH 7.00). The plates are then incubated for 1 hour at room temperaturewith shaking and then read on a BMG PheraStar Plus reader.

2) Human PI3K beta, delta and gamma isoforms are tested using theprocedure described for PI3K alpha above but with the following changes:PI3K beta (5.25 nM), PI3K delta (0.75 nM) and PI3K gamma (5 nM). Allisoforms supplied by Millennium Protein Science Group.

3) VPS34 is assayed using Adapta™ Universal Kinase Assay Kit(Invitrogen).

4) Human VPS34 enzyme assay method

100 mL compounds in DMSO are added to wells of a 384 well microtitreplate (Greiner 780076). At room temperature: 5 ul VPS34 reaction buffer(Invitrogen Assay Buffer Q (diluted 1 in 5 with nanopure water) plus 2mM DTT and 2 mM MnCl2) containing ATP (20 uM, Promega) and 200 uM PI-PSsubstrate (Invitrogen PV5122) is added followed immediately by 5 ulVPS34 reaction buffer (as above) containing VPS34 (5 nM, MillenniumProtein Sciences Group) and the mixture is incubated with shaking atroom temperature for 1 hour. Then 5 ul VPS34 stop-detect mix (as perInvitrogen Adapta Assay kit (PV5009) instructions (contains kinasequench buffer, TR-FRET buffer, Adapta Eu anti-ADP antibody and AlexaFluor 647 ADP tracer)) is added to quench the reaction. The plates arethen incubated for 30 minutes at room temperature with shaking and thenread on a BMG PheraStar Plus reader.

For the assay methods described above, test compound percent inhibition,at various concentrations, is calculated relative to control (DMSO andEDTA) treated samples. Compound concentration versus percent inhibitioncurves are fitted to generate IC₅₀ values. One skilled in the art willappreciate that the values generated either as percentage inhibition ata single concentration or IC₅₀ values are subject to experimentalvariation.

PI3K Cell Assays

1) In-Cell Western Assay

The pSer473 AKT LI-COR In-Cell Western Assay is a quantitativeimmunofluorescent assay that measures phosphorylation of serine 473 AKT(pSer473 AKT) in WM266.4 and SKOV3 tumor cell lines grown in cellculture.

WM266.4 cells are propagated in Minimum Essential Media (MEM)(Invitrogen) containing L-glutamine, 10% Fetal Bovine Serum, 1 mM MEMSodium Pyruvate, and 0.1 mM MEM Non-Essential Amino Acids and SKOV3cells are propagated in McCoy's 5A Media (modified) (Invitrogen)containing L-Glutamine and 10% Fetal Bovine Serum. Both cell lines arekept in a humidified chamber at 37° C. with 5% CO₂. For the pSer473 AKTLI-COR In-Cell Western Assay, 1.5×10⁴ WM266.4 and 1.5×10⁴ SKOV3 cellsare cultured in 100 μl of media per well in tissue culture-treatedblack-walled, clear bottom Optilux 96-well plates (BD Biosciences) for16-20 hours. Prior to addition of compounds, cell media is removed andreplaced with 75 μl of fresh media. Test compounds in DMSO are diluted1:100 in media. The diluted test compounds are added to the cells (25 μlper well) in 3-fold dilutions with a final concentration range of 0.0015to 10 μM. The cells are incubated for 2 hours in a humidified chamber at37° C. with 5% CO₂. Immediately following compound incubation, allliquid is removed from the wells and cells are fixed with 4%paraformaldehyde in PBS (150 μl per well) for 20 minutes at roomtemperature. The paraformaldehyde solution is removed from wells and thecells are permeabilized with 200 μA 0.1% Triton X-100 in PBS per wellfor 10 min×3 at room temperature. After removal of PBS+0.1% TritonX-100, 150 μA Odyssey blocking buffer (LI-COR Biosciences) is added toeach well and plates are incubated at room temperature for 1.5 h.Blocking buffer is removed from the wells and primary antibodies(Phospho-AKT (Ser473) (D9E) XP™ Rabbit mAb and AKT (pan) (40D4) MousemAb, Cell Signaling Technology) diluted in Odyssey blocking buffer areadded (50 μl per well). Plates are incubated at 4° C. overnight. Thecells are washed for 20 min×3 with PBS+0.1% Tween-20 (200 μA per well).Secondary antibodies (IRDye 680 Goat anti-Rabbit IgG (H+L) and IRDye800CW Goat anti-Mouse IgG (H+ L), LI-COR Biosciences) are diluted inOdyssey blocking buffer and added to wells (50 μl per well) followed bya 1 h incubation at room temperature, protected from light. Cells arewashed for 20 min×3 with PBS+0.1% Tween-20 (200 μl per well). Washbuffer is completely removed from wells after last wash, plates areprotected from light until scanned and analyzed with the OdysseyInfrared Imaging System (LI-COR Biosciences). Both pS473 AKT and AKT aresimultaneously visualized with the 680 nm fluorophore indicated by a redcolor and the 800 nm fluorophore indicated by a green color. Relativefluorescence units derived from the scans allow for quantitativeanalyses of both labeled proteins and the ratio of pS473 AKT to AKT iscalculated. Concentration response curves are generated by plotting theaverage ratios of PI3K inhibitor-treated samples relative toDMSO-treated controls to determine percent change in expression of pS473AKT, and percentage inhibition values at a single concentration orgrowth inhibition (IC₅₀) values are determined from those curves. Oneskilled in the art will appreciate that the values generated either aspercentage inhibition at a single concentration or IC₅₀ values aresubject to experimental variation.

2) ATPlite Viability Assay

The ATPLite™ Assay (Perkin-Elmer) measures cellularadenosine-triphosphate (ATP) through the generation of a luminescentsignal formed from the ATP-dependent enzyme firefly luciferase. Theluminescent signal intensity can be used as a measure of cellularproliferation, and can be used to assess the anti-proliferative effectsof PI3K inhibitors.

WM266.4 cells propagated in Minimum Essential Media (MEM) (Invitrogen)containing L-Glutamine, 10% Fetal Bovine Serum, 1 mM MEM SodiumPyruvate, and 0.1 mM MEM Non-Essential Amino Acids are cultured in384-well tissue culture-treated Black/Clear plates (Falcon) at 1×10³cells per well in a volume of 75 μl in a humidified chamber at 37° C.with 5% CO₂ for 24 h. Test compounds (2 μl in 100% DMSO) are diluted in95 μl of cell culture media. The diluted test compounds are added (8 μlper well) to 384-well plates. Final concentration range of 3-fold serialdilution of compounds is 0.001 to 20 μM. Plates are incubated for 72 hin a humidified chamber at 37° C. with 5% CO₂. One control plate withoutcompound addition is processed at the start of the 72 h incubation as a“Time Zero” reading for quantitative evaluation of cell viability atstart of assay. After 72 h, all but 25 μl of cell culture media isremoved from each well, followed by the addition of 25 μl of ATPlite1step reagent (Perkin Elmer) to each well. Luminescence is measured on aLEADSeeker Luminescence Counter (GE Healthcare Life Sciences).Concentration response curves are generated by calculating theluminescence decrease in test compound-treated samples relative toDMSO-treated controls, and percentage inhibition values at a singleconcentration or growth inhibition (IC₅₀) values are determined from thecurves. One skilled in the art will appreciate that the values generatedeither as percentage inhibition at a single concentration or IC₅₀ valuesare subject to experimental variation.

Vps34 Cell Assays

1) FYVE Domain Redistribution Assay

The FYVE domain redistribution assay monitors translocation ofEGFP-2×FYVE from its initial location bound to (PtdIns(3)P) in earlyendosomes to the cytoplasm in response to test compounds. RecombinantU2OS cells stable expressing the FYVE finger from the human homologue ofthe hepatocyte growth factor-regulated tyrosine kinase substrate Hrs,duplicated in tanden (GenBank Acc. NM_(—)004712) and fused to theC-terminus of enhanced green fluorescent protein (EGFP). U2OS cells areadherent epithelial cells derived from human osteosarcoma. Expression ofEGFP-2X-FYVE is controlled by a standard CMV promoter and continuosexpression is maintained by addition of geneticin to the culture medium.Localization of the fusion protein within the cells is imaged on theEvotec Technologies OPERA Confocal Imager and Integrated Spot Signal PerCellular Signal is quantified using Acapella software. Using thisinformation, percentage inhibition values at a single concentration orIC₅₀ values for inhibitors can be determined.

U2OS EGFP-2×FYVE cells are propagated in Dulbecco's Modified Eagle MediaHigh glucose (D-MEM) (Invitrogen cat. 11995) containing 10% Fetal BovineSerum (HyClone cat. SH30071.02) and 0.5 mg/ml Geneticin (Invitrogen) andkept in a humidified chamber at 37° C. with 5% CO₂. 8×10³ cells arecultured in 100 μl of media per well in tissue culture-treatedblack-walled, clear bottom Optilux 96-well plates (BD Biosciences) for16-24 hours.

Prior to addition of compounds, cell media is removed and replaced with75 μl of fresh media. Test compounds in DMSO are diluted 1:100 in media.The diluted test compounds are added to the cells (25 μl per well) in3-fold dilutions with a final concentration range of 0.0015 to 10 μM.The cells are incubated for 30 minutes in a humidified chamber at 37° C.with 5% CO₂. Immediately following compound incubation, all liquid isremoved from the wells and cells are fixed with 4% paraformaldehyde inPBS (75 μl per well) for 15 minutes at room temperature. Theparaformaldehyde solution is removed from wells and washed once with PBS(100 μl per well). The PBS is removed and cells are incubated with DRAQ5Nucleur Dye (Alexis/Biostatus) (85 μl per well). The plates are coveredwith Flash Plate plastic adhesive foil and imaged on the EvotecTechnologies OPERA Confocal Imager Opera after at least a 30 minuteincubation. Concentration curves are generated by calculating theIntegrated Spot Intensity Per Cellular Signal decrease in test-compoundtreated samples relative to DMSO-treated controls and a 100% controlinhibitor, and percentage inhibition values at a single concentration orgrowth inhibition (IC₅₀) values are determined from the curves. Oneskilled in the art will appreciate that the values generated either aspercentage inhibition at a single concentration or IC₅₀ values aresubject to experimental variation.

As detailed above, compounds of the invention inhibit PI3K and/or VPS34.Examples of class I PI3-kinase isoforms are PI3K α, β, γ and δ. Incertain embodiments, the compounds of the invention inhibit one or moreisoforms of PI3K. In certain other embodiments, the compounds of theinvention selectively inhibit one particular isoform of PI3K. Forexample, in some embodiments the compounds of the invention selectivelyinhibit PI3Kα. In some embodiments the compounds of the inventionselectively inhibit PI3Kβ.

As used herein, selective inhibitor refers to compounds that inhibit oneor more of the particular PI3K isoforms with at least about >10-fold, orat least about >20-fold, or at least about >30-fold selectivity for theone or more particular PI3K isoforms relative to other class IPI3-kinase isoforms in a biochemical assay. By way of example, compoundsthat inhibit PI3Kβ with at least about >10-fold, or at leastabout >20-fold, or at least about >30-fold selectivity relative to PI3Kα, γ or δ are selective inhibitors of PI3Kβ. Alternatively, compoundsthat inhibit PI3K β and δ with at least about >10-fold, or at leastabout >20-fold, or at least about >30-fold selectivity relative to PI3Kα or γ are selective inhibitors of PI3K β and δ.

As detailed above, compounds of the invention inhibit PI3K. In certainembodiments, compounds inhibit one or more isoforms of PI3K. In otherembodiments, compounds of the invention inhibit PI3Kalpha and have anIC₅₀>1.0 μM. For example, these compounds include 2, 3, 5, 6, 7, 8, 9,11, 12, 15, 16, 17, 18, 19, 21, 22, 23, 25, 26, 27, 33, 34, 36, 37, 39,43, 44, 45, 46, 47, 49, 51, 52, 55, 58, 59, 60, 62, 63, 65, 66, 68, 69,70, 73, 75, 76, 77, 78, 79, 80, 81, 84, 85, 87, 88, 89, 91, 92. In otherembodiments, compounds of the invention have an IC₅₀<1.0 μM but >0.1 μM.For example, these compounds include compounds 1, 4, 10, 14, 20, 24, 28,30, 31, 32, 35, 38, 40, 42, 48, 53, 54, 56, 57, 61, 64, 67, 71, 72, 74,82, 83, 86, 90. In still other embodiments, compounds of the inventionhave an IC₅₀<0.1 μM. For example, these compounds include compounds 13,29, 41, 50. In still other embodiments, compounds of the inventioninhibit PI3 Kbeta and have an IC₅₀>1.0 μM. For example, these compoundsinclude 2, 18, 22, 24, 29, 49, 55, 63, 67, 78. In other embodiments,compounds of the invention have an IC₅₀<1.0 μM but >0.1 μM. For example,these compounds include compounds 1, 4, 6, 8, 10, 12, 15, 17, 23, 25,26, 27, 28, 32, 33, 34, 35, 37, 38, 39, 40, 42, 46, 47, 48, 53, 54, 56,57, 58, 60, 61, 62, 64, 68, 69, 70, 71, 72, 73, 74, 76, 79, 82, 83, 84,89. In still other embodiments, compounds of the invention have anIC₅₀<0.1 μM. For example, these compounds include compounds 3, 5, 7, 9,11, 13, 14, 16, 19, 20, 21, 30, 31, 36, 41, 43, 44, 45, 50, 51, 52, 59,65, 66, 75, 77, 80, 81, 85, 86, 87, 88, 90, 91, 92.

In some embodiments, compounds of the invention inhibit PI3K α and β ata 1.1 μM concentration with the percent inhibition as shown in the tablebelow.

PI3Kα Percent PI3Kβ Percent Compound Inhibition Inhibition 91 27 105 939 80 94 58 97 95 68 101 96 58 109 97 53 101 98 58 111 99 12 72 100 20 98101 30 105 102 30 78 103 2 71 104 26 109 105 21 98 106 58 103 107 49 103108 44 100 109 6 76 110 5 41 111 7 77 112 95 110 113 25 100 114 40 106115 45 97 116 46 98 117 48 94 118 28 104 119 9 88 120 18 97 121 11 59122 49 106 123 64 105 124 79 109 125 46 99 126 42 103 127 40 110 128 46106

In some embodiments, compounds of the invention inhibit PI3K δ and γ ata 1.0 μM concentration with the percent inhibition as shown in the tablebelow.

PI3Kδ Percent PI3Kγ Percent Compound Inhibition Inhibition 91 84.8 15.493 46.0 9.5 94 102.4 52.6 95 86.1 23.9 96 96.0 36.2 97 89.8 17.8 98108.5 67.6 99 55.4 6.4 100 65.5 13.2 102 38.1 6.8 103 38.6 6.4 104 93.028.8 105 51.2 9.8 106 88.8 51.8 107 87.3 20.2 108 99.6 38.1 109 35.4 3.9111 60.5 6.9 112 114.5 69.0 113 78.8 32.5 114 112.8 56.9 115 63.0 12.0116 83.0 36.7 117 78.5 14.7 118 89.3 27.5 119 62.6 7.6 120 77.0 11.0 12177.3 7.3 122 96.2 49.6 123 96.8 36.6 124 112.0 74.2 125 85.1 25.9 126100.4 37.6 127 100.4 55.0 128 114.2 63.4

In some embodiments, compounds of the invention inhibit VPS34 at a 1.0μM concentration with the percent inhibition as shown in the tablesbelow.

VPS34 Percent Compound Inhibition 93 19.2 94 30.6 95 167.0 96 47.8 9745.0 98 68.9 99 46.7 100 36.6 102 28.2 103 7.2 104 63.2 105 22.6 10634.4 107 45.8 108 62.4 109 24.0 111 46.8 112 37.8 113 18.1 114 131.4 11539.7 116 54.2 117 28.6 118 68.2 119 19.5 120 38.3 121 64.8 122 55.2 12345.1 124 78.8 125 37.1 126 44.0 127 33.7 128 88.1

p110 alpha p110 beta p110 gamma p110 delta Percent Percent PercentPercent Compound Inhibition Inhibition Inhibition Inhibition 129 83 10632 109 130 21 73 22 62 131 75 78 5 80 132 45 103 53 77 133 84 101 26 74134 21 72 8 44 135 78 87 8 99 136 80 110 67 109 137 12 54 12 30 138 4386 13 69 139 77 100 24 105 140 76 47 62 74 141 17 89 15 66 142 15 67 747 143 58 115 62 85 144 63 94 19 111 145 64 98 9 97 146 67 103 23 110147 83 96 18 107 148 41 98 34 69 149 54 109 75 117 150 2 54 6 35 151 72105 17 108 152 61 97 16 106 153 75 84 11 87 154 79 108 39 108 155 29 6428 53 156 13 47 2 33 157 55 68 7 101 158 18 94 20 69 159 18 61 5 31 16074 101 20 107 161 14 60 7 40 162 38 93 33 83 163 97 110 25 106 164 100107 44 112 165 64 77 14 87 166 92 82 3 85 167 105 103 26 110 168 23 10758 110 169 65 89 7 65 170 84 106 26 105 171 59 106 60 99 172 28 101 6 60173 69 67 3 83 174 15 70 8 59 175 19 85 7 36 176 76 109 35 109 177 79100 34 106 178 20 109 38 88 179 29 60 5 89 180 60 102 21 102 181 85 9135 108 182 83 100 45 107 183 −2 16 3 9 184 76 112 16 112 185 16 97 9 50186 68 109 65 92 187 32 95 25 77 188 47 94 36 82 189 89 96 21 106 190 360 7 33 191 26 97 30 90 192 48 90 12 100 193 26 69 13 46 194 17 18 19552 74 8 88 196 69 91 12 105 197 15 23 4 19 198 18 108 35 70 199 21 64 1642 200 101 118 60 111 201 74 105 37 110 202 12 80 8 54 203 10 88 16 67204 70 101 25 90 205 42 114 64 83 206 90 96 11 106 207 27 83 9 51 208 42108 47 107 209 92 107 34 108 210 52 110 68 92 211 111 111 13 106 212 87109 38 112 213 57 80 35 109 214 46 84 14 46 215 29 85 8 51 216 64 91 1199 217 30 74 24 60 218 61 102 14 97 219 32 101 31 107 220 92 91 9 99 22162 94 8 100 222 68 98 9 102 223 67 94 21 102 224 70 92 15 103 225 51 5251 84 226 46 98 14 93 227 −2 76 3 24 228 24 94 11 57 229 62 105 16 106230 57 93 29 102 231 34 104 47 77 232 38 105 26 67 233 61 97 28 74 23460 100 10 104 235 65 101 17 66 236 11 53 10 48 237 61 89 238 72 88 11 96239 30 68 27 41 240 52 79 8 98 241 59 107 27 104 242 81 104 36 112 24312 66 4 45 244 77 101 14 101 245 73 109 15 104 246 15 81 8 43 247 83 10521 104 248 89 106 35 109 249 51 98 9 56 250 53 92 5 88 251 14 96 12 44252 58 85 12 60 253 20 64 2 27 254 49 96 8 91 255 0 55 5 39 256 25 87 857 257 31 97 30 68 258 18 86 13 47 259 69 100 25 101 260 37 74 6 37 26179 113 33 105 262 0 69 4 12 263 48 105 43 84 264 32 99 28 100 265 64 10964 111 266 36 90 8 52 267 100 113 43 111 268 82 95 16 102 269 72 100 15101 270 81 114 24 111 271 35 82 8 63 272 70 96 10 70 273 88 73 7 98 27498 109 38 107 275 17 47 14 44 276 4 15 6 12 277 95 97 55 116 278 23 9835 83 279 19 106 42 78 280 35 106 34 92 281 52 96 56 97 282 14 99 21 64283 96 98 18 99 284 39 114 66 110 285 16 83 18 77 286 36 92 50 104 28784 109 69 112 288 14 85 19 76 289 11 32 10 32 290 23 104 49 104 291 36107 57 105 292 4 82 6 56 293 98 108 78 110 294 47 94 35 101 295 101 11176 112 296 37 79 14 107 297 26 104 33 77 298 11 95 38 103 299 39 109 42108 300 44 105 46 97 301 55 107 49 89 302 21 100 15 97 303 99 110 69 115304 6 25 7 32 305 37 106 37 74 306 81 109 51 108 307 15 84 9 62 308 41106 39 92 309 56 101 66 108 310 34 106 64 105 311 55 104 64 105 312 64105 47 92 313 73 117 30 86 314 42 109 42 104 315 97 110 75 114 316 78106 62 111 317 20 77 29 70 318 18 96 14 76 319 59 105 50 113 320 16 9435 97 321 67 73 59 86 322 64 104 28 67 323 66 61 46 97 324 107 118 67113 325 17 89 22 89 326 79 108 56 96 327 34 109 22 109 328 11 98 48 83329 39 112 29 80 330 85 109 61 106 331 37 105 51 107 332 11 77 27 91 33363 95 55 74 334 21 103 12 101 335 54 111 31 107 336 16 90 10 49 337 1460 11 46 338 67 110 73 109 339 20 86 12 55 340 48 113 59 104 341 30 11030 98 342 34 80 12 97 343 84 110 67 113 344 24 103 59 102 345 64 105 6283 346 21 98 23 98 347 71 102 60 111 348 4 63 4 56 349 43 108 42 96 3506 58 3 41 351 15 82 46 79 352 18 85 14 84 353 19 87 15 80 354 89 111 4099 355 44 100 53 105 356 11 95 23 72 357 89 110 79 110 358 13 43 32 51359 90 109 64 102 360 30 106 49 110 361 104 115 60 111 362 80 116 44 104363 99 113 65 106 364 88 109 56 101 365 105 117 63 112 366 66 113 77 113367 99 110 72 116 368 89 112 87 113 369 109 115 65 109 370 22 98 12 62

While we have described a number of embodiments of this invention, it isapparent that our basic examples may be altered to provide otherembodiments, which utilize the compounds and methods of this invention.Therefore, it will be appreciated that the scope of this invention is tobe defined by the appended claims rather than by the specificembodiments, which have been represented by way of example.

1-73. (canceled)
 74. A compound of formula IA or IB:

or a pharmaceutically acceptable salt thereof, wherein: R¹ is—C(O)N(R³)₂, —C(O)(NH)OH, —C(═NH)NHOH, —C(O)NR³N(R³)₂, —C(═N—NH₂)NH₂, or—C(═N)N(R³)₂; each occurrence of R³ is independently hydrogen or anoptionally substituted C₁₋₆aliphatic; Ring A is a group selected from3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-5heteroatoms independently selected from nitrogen, oxygen, and sulfur,6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatomsindependently selected from nitrogen, oxygen, and sulfur; eachoccurrence of R² is independently R^(12a), -T₂-R^(12d), or—V₂-T₂-R^(12a), and: each occurrence of R^(12a) is independentlyhalogen, —CN, —NO₂, —R^(12c), —N(R^(12b))₂, —OR^(12b), —SR^(12c),—S(O)₂R^(12c), —C(O)R^(12b), —C(O)OR^(12b), —C(O)N(R^(12b))₂,—S(O)₂N(R^(12b))₂, —OC(O)N(R^(12b))₂, —N(R^(12e))C(O)R^(12b),—N(R^(12e))SO₂R^(12c), —N(R^(12e))C(O)OR^(12b),—N(R^(12e))C(O)N(R^(12b))₂, or N(R^(12e))SO₂N(R^(12b))₂, or twooccurrences of R^(12b), taken together with a nitrogen atom to whichthey are bound, form an optionally substituted 4-7-membered heterocyclylring having 0-1 additional heteroatoms selected from nitrogen, oxygen,and sulfur; each occurrence of R^(12b) is independently hydrogen or anoptionally substituted group selected from C₁-C₆ aliphatic,3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-5heteroatoms independently selected from nitrogen, oxygen, and sulfur,6-10-membered aryl, and 5-10-membered heteroaryl having 1-5 heteroatomsindependently selected from nitrogen, oxygen, and sulfur; eachoccurrence of R^(12c) is independently an optionally substituted groupselected from C₁-C₆ aliphatic, 3-10-membered cycloaliphatic,4-10-membered heterocyclyl having 1-5 heteroatoms independently selectedfrom nitrogen, oxygen, and sulfur, 6-10-membered aryl, and 5-10-memberedheteroaryl having 1-5 heteroatoms independently selected from nitrogen,oxygen, and sulfur; each occurrence of R^(12d) is independently hydrogenor an optionally substituted from 3-10-membered cycloaliphatic,4-10-membered heterocyclyl having 1-5 heteroatoms independently selectedfrom nitrogen, oxygen, and sulfur, 6-10-membered aryl, or 5-10-memberedheteroaryl having 1-5 heteroatoms independently selected from nitrogen,oxygen, and sulfur; each occurrence of R^(12e) is independently hydrogenor an optionally substituted C₁₋₆ aliphatic group; each occurrence of V₂is independently —N(R^(12e))—, —O—, —S—, —S(O)—, —S(O)₂—, —C(O)—,—C(O)O—, —C(O)N(R^(12e))—, —S(O)₂N(R^(12e))—, —OC(O)N(R^(12e))—,N(R^(12e))C(O)—, —N(R^(12e))SO₂—, —N(R^(12e))C(O)O—,—N(R^(12e))C(O)N(R^(12e))—, —N(R^(12e))SO₂N(R^(12e))—, —OC(O)—, or—C(O)N(R^(12e))—O—; and T₂ is an optionally substituted C₁-C₆ alkylenechain wherein the alkylene chain optionally is interrupted by —N(R¹³)—,—O—, —S—, —S(O)—, —S(O)₂—, —C(O)—, —C(O)O—, —C(O)N(R¹³)—, —S(O)₂N(R¹³)—,—OC(O)N(R¹³)—, —N(R¹³)C(O)—, —N(R¹³)SO₂—, —N(R¹³)C(O)O—,—N(R¹³)C(O)N(R¹³)—, —N(R¹³)S(O)₂N(R¹³)—, —OC(O)—, or —C(O)N(R¹³)—O— orwherein T₂ or a portion thereof optionally forms part of an optionallysubstituted 3-7 membered cycloaliphatic or heterocyclyl ring, whereinR¹³ is hydrogen or an optionally substituted C₁₋₄aliphatic group; n is 0to 4; W is selected from —C(R⁷)₂—, —C(═C(R⁷)₂)—, —C(R⁷)₂O—,—C(R⁷)₂NR^(7a)—, —O—, —N(R^(7b))—, —S—, —S(O)—, —S(O)₂—, —C(O)—,—C(O)NR^(7a)—, and —N(R^(7a))C(O)—, wherein: each occurrence of R⁷ isindependently hydrogen, or an optionally substituted group selected fromC₁₋₆ aliphatic, 6-10-membered aryl, 5-10-membered heteroaryl having 1-5heteroatoms independently selected from nitrogen, oxygen, and sulfur,—N(R^(7b))₂, —OR^(7a), —SR^(7a), halo, and —CN; each occurrence ofR^(7a) is independently hydrogen or optionally substituted C₁₋₆aliphatic or optionally substituted C₃₋₆ cycloaliphatic; each occurrenceof R^(7b) is independently hydrogen, optionally substituted C₁₋₆aliphatic, optionally substituted C₃₋₆ cycloaliphatic, —C(O)R^(7a),—C(O)OR^(7a), S(O)R^(7a), or —S(O)₂R^(7a); or wherein any twooccurrences of R⁷, R^(7a), or R^(7b) taken together with the atom towhich they are bound, form an optionally substituted group selected froma 3-6-membered cycloaliphatic ring, 6-10-membered aryl, 3-6-memberedheterocyclyl having 1-5 heteroatoms independently selected fromnitrogen, oxygen, and sulfur, and 5-10-membered heteroaryl having 1-5heteroatoms independently selected from nitrogen, oxygen, and sulfur; orwherein any two occurrences of R^(7a) and R², or R^(7b) and R² takentogether with the nitrogen atom to which they are bound, form anoptionally substituted group selected from 3-6-membered heterocyclylhaving 1-5 heteroatoms independently selected from nitrogen, oxygen, andsulfur, and 5-10-membered heteroaryl having 1-5 heteroatomsindependently selected from nitrogen, oxygen, and sulfur; G₁ is N; andHY is

wherein each occurrence of R¹⁴ is independently —R^(14a) or -T₁-R^(14d),wherein: each occurrence of R^(14a), as valency and stability permit, isindependently fluorine, ═O, ═S, —CN, —NO₂, —R^(14c), N(R^(14b))₂,—OR^(14b), SR^(14c), —S(O)₂R^(14c), —C(O)R^(14b), —C(O)OR^(14b),—C(O)N(R^(14b))₂, —S(O)₂N(R¹⁴)₂, —OC(O)N(R¹⁴)₂, —N(R^(14e))C(O)R^(14b),—N(R^(14e))SO₂R^(14c), —N(R^(14e))C(O)OR^(14b),—N(R^(14e))C(O)N(R^(14b))₂, or —N(R^(14e))SO₂N(R^(14b))₂, or twooccurrences of R^(14b), taken together with a nitrogen atom to whichthey are bound, form an optionally substituted 4-7-membered heterocyclylring having 0-1 additional heteroatoms selected from nitrogen, oxygen,and sulfur; each occurrence of R^(14b) is independently hydrogen or anoptionally substituted group selected from C₁-C₆ aliphatic,3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-5heteroatoms independently selected from nitrogen, oxygen, and sulfur,6-10-membered aryl, and 5-10-membered heteroaryl having 1-5 heteroatomsindependently selected from nitrogen, oxygen, and sulfur; eachoccurrence of R^(14c) is independently an optionally substituted groupselected from C₁-C₆ aliphatic, 3-10-membered cycloaliphatic,4-10-membered heterocyclyl having 1-5 heteroatoms independently selectedfrom nitrogen, oxygen, and sulfur, 6-10-membered aryl, and 5-10-memberedheteroaryl having 1-5 heteroatoms independently selected from nitrogen,oxygen, and sulfur; each occurrence of R^(14d) is independently hydrogenor an optionally substituted from 3-10-membered cycloaliphatic,4-10-membered heterocyclyl having 1-5 heteroatoms independently selectedfrom nitrogen, oxygen, and sulfur, 6-10-membered aryl, or 5-10-memberedheteroaryl having 1-5 heteroatoms independently selected from nitrogen,oxygen, and sulfur; each occurrence of R^(14e) is independently hydrogenor an optionally substituted C₁₋₆ aliphatic group; and T₁ is anoptionally substituted C₁-C₆ alkylene chain wherein the alkylene chainoptionally is interrupted by —N(R^(14a))—, —O—, —S—, —S(O)—, —S(O)₂—,—C(O)—, —C(O)O—, —C(O)N(R^(14a))—, —S(O)₂N(R^(14a))—, —OC(O)N(R^(14a))—,—N(R^(14a))C(O)—, —N(R^(14a))SO₂—, —N(R^(14a))C(O)O—,—NR^(14a)C(O)N(R^(14a))—, —N(R^(14a))S(O)₂N(R^(14a))—, —OC(O)—, or—C(O)N(R^(14a))—O— or wherein T₁ or a portion thereof optionally formspart of an optionally substituted 3-7 membered cycloaliphatic orheterocyclyl ring; n is 0-6; m is 1 or 2; p is 0, 1, or
 2. 75. Thecompound of claim 74, wherein HY is

wherein both occurrences of m are
 1. 76. The compound of claim 74,wherein W is —C(R⁷)₂—, wherein one occurrence of R⁷ is hydrogen and theother occurrence of R⁷ is hydrogen, optionally substituted C₁₋₆aliphatic, —N(R^(7b))₂, —OR^(7a), —SR^(7a), halo, or —CN; and whereineach occurrence of R^(7a) is independently hydrogen or optionallysubstituted C₁₋₆ aliphatic; and each occurrence of R^(7b) isindependently hydrogen, optionally substituted C₁₋₆ aliphatic,—C(O)R^(7a), or —S(O)₂R^(7a); or wherein two occurrences of R^(7b),taken together with the nitrogen atom to which they are bound, form anoptionally substituted 3-6-membered heterocyclic ring.
 77. The compoundof claim 74, wherein W is —C(H)(N(R^(7b))₂)—, —CH₂—, —C(H)(OR^(7a))—,—NR^(7b)—, or —N(R^(7a))C(O)—, wherein each occurrence of R^(7a) isindependently hydrogen or optionally substituted C₁₋₆ aliphatic; andeach occurrence of R^(7b) is independently hydrogen or optionallysubstituted C₁₋₆ aliphatic.
 78. The compound of claim 74, wherein Ring Ais 6-10-membered aryl or 5-10-membered heteroaryl having 1-5 heteroatomsindependently selected from nitrogen, oxygen, and sulfur; and n is 0 to3.
 79. The compound of claim 74, wherein ring A is a group selectedfrom:

wherein ring A is optionally further substituted by n occurrences of R²,and wherein R^(2a) is hydrogen or an optionally substituted groupselected from C₁₋₆aliphatic, 3-10-membered cycloaliphatic, 4-10-memberedheterocyclyl having 1-5 heteroatoms independently selected fromnitrogen, oxygen, and sulfur, 6-10-membered aryl, and 5-10-memberedheteroaryl having 1-5 heteroatoms independently selected from nitrogen,oxygen, and sulfur.
 80. The compound of claim 74, wherein Ring A is agroup selected from:

wherein ring A is optionally further substituted by n occurrences of R²,and wherein R^(2a) is hydrogen or an optionally substituted groupselected from C₁₋₆aliphatic, 3-10-membered cycloaliphatic, 4-10-memberedheterocyclyl having 1-5 heteroatoms independently selected fromnitrogen, oxygen, and sulfur, 6-10-membered aryl, and 5-10-memberedheteroaryl having 1-5 heteroatoms independently selected from nitrogen,oxygen, and sulfur.
 81. The compound of claim 74, wherein ring A is anaphthyl group; each occurrence of R² is independently halogen, C₁₋₃alkyl, —CN, C₁₋₃ haloalkyl, —OC₁₋₃ alkyl, —OC₁₋₃haloalkyl, —NHC(O)C₁₋₃alkyl, —NHC(O)NHC₁₋₃ alkyl, —NHS(O)₂C₁₋₃ alkyl, or —C(O)H; and n is 0 to3.
 82. The compound of claim 74, wherein ring A is a naphthyl group, R²is halogen and n is 1 to
 2. 83. The compound of claim 74, wherein Ring Ais a phenyl group; each occurrence of R² is independently halogen, C₁₋₃alkyl, —CN, C₁₋₃haloalkyl, —OC₁₋₃ alkyl, —OC₁₋₃haloalkyl, —NHC(O)C₁₋₃alkyl, —NHC(O)NHC₁₋₃ alkyl, —NHS(O)₂C₁₋₃ alkyl, or —C(O)H; and n is 0 to3.
 84. The compound of claim 74, wherein Ring A is a phenyl group, R² ishalogen and n is 1 to
 2. 85. A pharmaceutical composition comprising thecompound of claim 74, or a pharmaceutically acceptable salt thereof, anda pharmaceutically acceptable carrier, adjuvant, or vehicle.
 86. Acompound selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.
 87. A method of treatinga proliferative disorder in a patient comprising administering to saidpatient a therapeutically effective amount of the compound of claim 74,or a pharmaceutically acceptable salt thereof.
 88. The method of claim87, wherein the proliferative disorder is breast cancer, bladder cancer,colon cancer, glioma, glioblastoma, lung cancer, hepatocellular cancer,gastric cancer, melanoma, thyroid cancer, endometrial cancer, renalcancer, cervical cancer, pancreatic cancer, esophageal cancer, prostatecancer, brain cancer, or ovarian cancer.
 89. A method of treating aninflammatory or cardiovascular disorder in a patient comprisingadministering to said patient a therapeutically effective amount of thecompound of claim 74, or a pharmaceutically acceptable salt thereof. 90.The method of claim 89, wherein the inflammatory or cardiovasculardisorder is selected from allergies/anaphylaxis, acute and chronicinflammation, rheumatoid arthritis, autoimmunity disorders, thrombosis,hypertension, cardiac hypertrophy, and heart failure.
 91. A method forinhibiting PI3K or VPS34 activity in a patient comprising administeringa composition comprising a therapeutically effective amount of thecompound of claim 74, or a pharmaceutically acceptable salt thereof.